promise& progress - johns hopkins hospital · 2012/2013 promise& progress transformin g...

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PROMISE&PROGRESS

TRANSFORMING PROSTATE CANCERDETECTION, DIAGNOSIS, AND TREATMENT

THE S I DNEY K IMMEL COMPREHENS I VE CANCER CENTER AT JOHNS HOPK INS

Promise & Progress is published by The Sidney Kimmel ComprehensiveCancer Center at Johns HopkinsOffice of Public Affairs901 South Bond StreetSuite 573Baltimore, Maryland 21231(410) 955-1287

William G. Nelson, M.D., Ph.D.Director

Amy MoneDirector of Public Affairs

Valerie Matthews MehlEditor and Sr. [email protected]

Michelle PotterProduction Manager and Editorial Assistant

Vanessa WastaAssociate Director, Media Relationsand Web Projects

Keith WellerFeature Photography

Peter HowardCover Photography

MSK Partners, Inc.Design and Production

Printed in the USA

PROMISE&PROGRESS06

Headline MakersThe latest research from

the Kimmel Cancer Center

including new discoveries

in cancer treatments and

half-matched transplants

that may cure sickle cell

disease.

In The NewsNoteworthy progress,

new appointments, and

other cancer news.

PhilanthropyGifts and donations that

are funding our cancer

research and advancing

clinical care.

C O N T E N T S O N T H E W E B

02 34

On the Cover: Former Temptations singer Damon Harris, at his Owings Mills home.

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12012/2013 PROMISE&PROGRESS

THE KIMMEL CANCER Center is anincredible cancer discovery engine. Ourlaboratory scientists have made world-class findings that have revolutionizedcancer research. Still, what we are mostproud of is how we are using these break-throughs to improve the experience andoutcomes of patients. This only occurswhen scientists work side by side withclinicians, and this is the Kimmel CancerCenter model. A new clinical arm of ourgenetic and epigenetic sequencing labora-tories (see page 40) is focused on translat-ing these revolutionary discoveries aboutthe unique molecular blueprints of cancersinto clinical tests that will help identifythose people most at risk and guide diagnosis and treatment.

We are not content with the status quo.With discovery comes the opportunity,and I believe the obligation, to re-evaluateand improve how we deliver cancer care.In this issue, you will read about signifi-cant advances in how we detect, diagnoseand treat prostate cancer. We recognizedthat this is a disease that is too frequentlyoverdetected and overtreated but, at thesame time, is a leading killer of men. Withthe multidisciplinary expertise of some ofthe world’s best urologists, oncologists,radiation oncologists, pathologists, radiol-ogists, and cancer scientists we are trans-forming how prostate cancer screening and

treatment is delivered with evidence-based,personalized care that gets interventionsto patients who we know will benefit andmoves them away from those we knowwill only be harmed. At the same time, weare using the clinical characteristics thatdistinguish one group from the other todevelop novel prevention approaches, better screening and diagnostic markers,and more effective treatments.As a prostate cancer clinician-scientist,

and a member of this team, I am so proudof this work. As the Kimmel Cancer CenterDirector, I am excited about the possibili-ties because I recognize that much of whatwe learned about prostate cancer can beapplied to make similar advances againstother cancer types.

Our ability to make these unprecedentedgains is tied directly to the generosity ofour donors. The National Cancer Institute,the Department of Defense, Sidney Kimmel,David H. Koch, the CommonwealthFoundation for Cancer Research, theProstate Cancer Foundation, Safeway,Jones Day, AEGON, the Patrick C. WalshProstate Cancer Research Fund, theMaryland Cigarette Restitution Fund, and many dedicated individual donorsare among the contributors who havemade the Johns Hopkins prostate cancerprogram one of the strongest and mostproductive in the world.

Johns Hopkins clinicians and scientistshave a long history of pioneering advancesagainst prostate cancer. It was here thatthe first radical prostatectomy was per-formed, and here that it was reinvented.Here, laboratory scientists developed thefirst animal models to characterize theproperties and types of prostate cancer,and here, current researchers and clinicians build upon this work to deliver21st century personalized cancer medicine.This bench-to-bedside tradition is whatsets Johns Hopkins apart and ensurescontinued progress against prostate cancer and all cancers.

William G. Nelson, M.D., Ph.D.Marion I. Knott Professor and DirectorThe Sidney Kimmel ComprehensiveCancer Center at Johns Hopkins

D I R E C T O R ’ S L E T T E R

REDEFINING CANCER

WE ARE NOT CONTENT WITH THE STATUS QUO.WITH DISCOVERY COMES THE OPPORTUNITY, ANDI BELIEVE THE OBLIGATION, TO RE-EVALUATEAND IMPROVE HOW WE DELIVER CANCER CARE.

2 PROMISE&PROGRESS 2012/2013

HEADLINE MAKERSTHE LATEST RESEARCH from the JOHNS HOPKINS KIMMEL CANCER CENTER

HALF-MATCHEDTRANSPLANTS MAY CURESICKLE CELL DISEASEBlood, September 6, 2012

Kimmel Cancer Center bone marrowtransplant researcher Javier Bolanos-Meade, M.D., and team have shown

that half-matched (hap-loidentical) bone mar-row transplants cancure sickle cell anemia,a painful and debilitat-ing blood-forming dis-ease in which red blood

cells are shaped like crescents instead ofdiscs and clog blood vessels, cutting offoxygen to tissues and organs. Bone marrow transplant replaces the

diseased marrow with the healthy marrowof a donor. After an average of two yearsof follow-up, eight of 14 patients treatedwith a half-identical transplant andanother three who all received a fullymatched bone marrow transplant remainsymptom free. Ten patients are believedto be cured of their sickle cell disease. Patients with severe sickle cell disease

(SCD) face shortened life spans, intractablepain and eventual organ damage as aresult of their disease. SCD primarilyaffects African Americans. Most patientsdie before age 50, and many suffer poorquality of life with frequent episodes of“off-the-charts” pain, and an increasedrisk for kidney failure, stroke, deep-veinthrombosis, and lung disease. The abilityto safely use half-matching donors (parents,most siblings,and all chil-dren of thepatient) makesbone marrowtransplant aneffective optionfor the majori-ty of sickle cellpatients. Kimmel Cancer investigatorsEphraim Fuchs, M.D., and Leo Luznik,M.D., pioneered the haploidentical versionof the therapy to help patients who do nothave matching donors.

“We’re trying to reformat the bloodsystem and give patients new blood cells

to replace the diseasedones, much like youwould replace a com-puter’s circuitry with anentirely new harddrive,” says RobertBrodsky, M.D.,

Director of Hematology and The JohnsHopkins Family Professor of Medicine andOncology. “While bone marrow transplantshave long been known to cure sickle celldisease, only a small percentage of patientshave fully matched, eligible donors.” Six of the transplants were not suc-

cessful. The patients own diseased bloodcells eventually returned. Work to improvethe rate of bone marrow engraftment inhalf-identical transplants for sickle cell isongoing.Funding for the research was provided by

the National Cancer Institute and NationalInstitutes of Health grants P01CA15396 andK23HL083089 and Sistema Nacional deInvestigadores (Mexico). •EMBRYO GENE LINKED TOLETHAL LUNG CANCER Nature Genetics, September 2, 2012

Scientists from several institutions, led byresearchers at the Kimmel Cancer Center,completed a comprehensive map of thegenetic mutations linked to a lethal type

of lung cancer, known as small cell lungcancer (SCLC). “Small cell lung cancersare very aggressive. Most are found late,when the cancer has spread, and typicallysurvival is less than a year after diagno-sis,” says Charles Rudin, M.D., Ph.D.,professor of oncology and Director of theKimmel Cancer Center Lung CancerTherapeutics Program. “Our genomicstudies may help identify genetic pathwaysresponsible for the disease and give usnew ideas on developing drugs to treat it.”Among the genetic alterations identified

by the investigators was an increase in thenumber of copies (amplification) of a genecalled SOX2. Normal cells should containjust two copies of the gene (one copy fromeach parent), which is involved in embryodevelopment. In cancer, researchers sus-pect that amplification causes an overpro-duction of SOX2 proteins that, in turn,reignites and sustains cell growth associ-ated with tumor formation. “SOX2 is animportant clue in finding new ways totreat small cell lung cancer,” says Rudin.“We may be able to link a patient’s out-come to this gene and develop a drug totarget it or other genes it regulates.”

The research was funded by the BurroughsWellcome Fund, the Flight Attendant MedicalResearch Institute, the National CancerInstitute grants P50CA058184, P50CA70907,and P50CA058187, the CAPES Foundation,and the Ministry of Education of Brazil. •

Bolanos-Meade

Brodsky

Fuchs and Luznik

The crescent-shaped red bloodcells of sickle cell anemia


UPDATE:NOVEL TECHNIQUEREVERTS CELL TOEMBRYONIC STATEPublic Library of Science, August 8, 2012

The same scientist who last year trans-formed human blood cells into beatingheart cells has now developed a safe andsuper efficient method to turn the clockback on blood cells, reverting them to theprimitive state from which they derived.This form, known as the stem cell state, isthe point at which blood cells may developinto any other type of cell in the body.The work by Elias Zambidis, M.D.,

Ph.D., assistant professor of oncology and pediatrics at theInstitute for CellEngineering and theKimmel Cancer Centeris the latest work in hisongoing effort to effi-ciently and consistently

convert adult blood cells into stem cellsthat can be used for clinical research inplace of human embryonic stem cells.“Taking a cell from an adult and con-verting it all the way back to the way itwas when that person was a 6-day-oldembryo creates a completely new biology toward our understanding of how cells age and what happenswhen things go wrong, as in cancerdevelopment,” Zambidis says.More common methods use viruses

to convert cells to a stem cell state, andamong hundreds of blood cells, they typically obtain a successful conversion in one to two cells. Zambidis chose not to use viruses because they can mutategenes and initiate cancers—the very disease he is working to fight—in newlytransformed cells. Instead, he and histeam opted to use plasmids, rings of DNAthat replicate briefly inside cells and thendegrade, and umbilical cord blood treatedwith growth factors to transform cells tothe primitive stem cell state. This tech-nique resulted in a successful conversionof 50 to 60 percent of cells.The work was supported by the National

Institutes of Health National Heart, Lung,and Blood Institute, grants 1U01HL099775and U01HL100397, the National CancerInstitute grant CA60441, and the MarylandStem Cell Research Fund grants2011-MSCRFII-0008-00 and 2007-MSCRF II-0379-00. •

DETECTABLE LESIONSWARN OF HEREDITARYPANCREAS CANCER Gastroenterology, April 2012

A Johns Hopkins-led study of 216 adultsat high risk for hereditary pancreas cancerfound that more than four in 10 peoplehave small lesions in their pancreas longbefore they have any symptoms of thedeadly disease. The prevalence of thelesions increases with age, and are mostcommon in people age 50 and older.Ultrasound done by endoscopy was better than MRI and significantly betterthan CT scans at finding these potentialprecursors to pancreas cancer.

Endoscopic ultrasounddetected lesions in 42.6 percent of studyparticipants, versus 33percent with MRI and 11 percent with CT. Infive patients, precancer-

ous lesions that likely would have goneundetected were identified and treated.About 10 to 15 percent of all pancreas

cancers are hereditary. This research, ledby Marcia Irene Canto, M.D., M.H.S.,professor of gastroenterology and oncolo-gy, could help reduce the death rate fromhereditary pancreas cancer, which is generally fatal once these lesions begin to grow and symptoms appear. “We now know that although these high-riskpatients often tend to develop pancreaticlesions, we can detect the lesions, trackthem over time and remove them beforethey become cancer,” says Canto. Not all pancreatic cysts become

pancreas cancer. Earlier research by BertVogelstein, M.D., and his team in theLudwig Center for Cancer Genetics, aredeveloping biomarkers that predict themalignant potential of cysts. Researchershope those findings used in conjunctionwith the results from this new study willhelp experts find and treat potentiallylethal pancreas cancers while they are still curable.The research was supported by the

National Cancer Institute Specialized Programsof Research Excellence (SPORE), TheLustgarten Foundation for Pancreatic CancerResearch, The Michael Rolfe Foundation,Olympus Corporation, Cooke Medical, theKarp Family, H.H. & M. Metals Inc. Fundfor Cancer Research and ChiRhoClin, Inc. •

DRUG TREATMENTREPROGRAMS CANCERCELLSCancer Cell, March 20, 2012

Experimenting with cells in culture,researchers obtained promising resultswith two drugs once considered too toxicfor human cancer treatment. The drugs,azacitidine (AZA) and decitabine (DAC),are epigenetic-targeted drugs and work tocorrect cancer-causing biochemical alter-ations to the environment of DNA.The researchers said the drugs also

were found to take aim at a small but dangerous subpopulation of self-renew-ing cells, sometimes referred to as cancerstem cells, which evade most cancerdrugs and cause recurrence and spread.The study produced evidence that low dosesof the drugs could cause antitumor respons-es in breast, lung, and colon cancers.Conventional chemotherapy agents

work by indiscriminately poisoning andkilling rapidly dividing cells, includingcancer cells, by damaging cellular machin-ery and DNA. “In contrast, low doses of

AZA and DAC may re-activate genes thatstop cancer growthwithout causing imme-diate cell-killing or DNAdamage,” says StephenBaylin, M.D., Ludwig

Professor of Oncology and DeputyDirector of the Kimmel Cancer Center.Baylin and his colleague Cynthia

Zahnow, Ph.D., assistant professor ofoncology and the Evelyn Grolman GlickScholar, decided to take another look at

the drugs after they hadshowed benefit at lowdoses in patients with apre-leukemic disordercalled myelodysplasticsyndrome (MDS). Theirnew work revealed that

the low-dose therapy reversed cancer cellgene pathways, including those control-ling cell cycle, cell repair, cell maturation,cell differentiation, immune cell interac-tion, and cell death. Effects varied amongindividual tumor cells, but the scientistsgenerally saw that cancer cells reverted toa more normal state and eventually died. The results of clinical trials in lung

cancer, led by Charles Rudin, M.D.,Ph.D., professor of oncology and Director

Zambidis

Canto

Baylin

Zahnow


HEADLINE MAKERS

NEW FINDINGS ON BRCA1BREAST CANCER GENEKimmel Cancer Center breast can-cer researchers have showed thatthe inactivation of a single copy ofthe breast cancer gene BRCA1leaves breast cells vulnerable tocancer by reducing their ability torepair DNA damage, causinggenetic instability, the hallmark ofcancer. An inherited mutation inBRCA1 is the leading risk factor forhereditary breast cancer, promptingpreventive mastectomies or closemonitoring. Learn how these newfindings may aid development ofdrugs to prevent hereditary breastcancer and tools to identify womenwho benefit most from prophylactictreatments.

SEQUENCING OURGENES: IS CANCERWRITTEN IN OUR DNA?Technology called next generationsequencing can be used to revealan individual’s complete and entireDNA (whole genome). Right now,it costs about $5000 to sequencean individual’s whole genome, butthe price tag is decreasing rapidly.With its increasing affordability, manyhave suggested that it could be usedto identify individuals who were likelyto develop cancer in the future aswell as those who would be safefrom the disease. But, will it?

PROVOKING AN IMMUNERESPONSE TO CANCERBreakthrough discoveries haverevealed an immune inhibitorycheckpoint called PD-1 that is co-opted by tumors to shut down animmune response to cancer cells.Two clinical trials that used anti-bodies to block PD-1 and a relatedresulted in significant and longlasting responses againstmelanoma skin cancer, renal cell(kidney) cancer, and lung cancer.Read the story on page 40.

PREDICTING WHICHLUNG CANCER DRUGSWILL WORKResearchers showed that DNAchanges in a gene that drives thegrowth of one type of lung cancercould make cancers cells resistantto treatment. The findings indicatewhich classes of drugs won’t workand which ones may be the mosteffective. Learn more.

THE LIFE CLINICThe Life Clinic at the JohnsHopkins Kimmel Cancer Centerassesses and monitors cancer survivors to help manage long termcomplications from previous cancertreatments.

BRAIN CANCER EXPERTSSET THE RECORD STRAIGHTOncotarget, January 2012

Laboratory findings from Kimmel CancerCenter brain cancer researchers refuteoutside studies that suggest blood vesselsthat form within brain cancers are largelymade up of cancer cells. “We don’t ques-

tion whether brain can-cer cells have the poten-tial to express bloodvessel markers and mayoccasionally find theirway into blood vessels,but we do question the

extent to which this happens,” saysCharles Eberhart, M.D., Ph.D., chief ofneuropathology and professor of patholo-gy, ophthalmology, and oncology. “Ingeneral, we find no evidence in our studythat these vessels contain substantialamounts of cancer cells.”Eberhart became aware of claims about

the cancerous nature of tumor blood vessels when students solicited his opinionon journal articles on the topic. “My firstreaction to this research was ‘How couldthis be true?’” says Eberhart. “Our clinicalexperience examining tissue from braincancers does not support it.”Research has long demonstrated that

malignant brain tumors contain largenumbers of blood vessels to feed their

growing demand for nutrients. The bloodvessels are formed when tumors pumpout growth factors that increase vesselproduction. Such studies opened the doorto treatment strategies that specificallytargeted blood-vessel growth and the vessel cells themselves. More recently,scientists in Italy and at the MemorialSloan Kettering Cancer Center in NewYork published results of studies suggest-ing that these tumor blood vessels are madeby primitive types of brain cancer cellsand were more prone to drug resistance. Eberhart teamed up with colleagues at

the Dana Farber Cancer Institute andHarvard Medical School to examine themolecular features of brain cancer cellsfrom 100 patients and used biomarkers aswell as known brain-cancer related genemutations to distinguish normal vascularcells from cancer cells. They found thatonly 10 percent of the samples containedvascular cells that had cancer gene muta-tions, and in those rare tumor samples,only a few cells were affected. These findings, that refute the preva-

lence of cancer-like blood vessels, call intoquestion the use and value of anticancerdrugs that target blood vessels in braincancer patients.Funding for the study was provided by the

National Institutes of Health grantsT32CA067751 and 5R01NS055089. •

of the Lung Cancer Therapeutics Program,and published in 2011 in Cancer Discovery,also indicate that the drugs make tumorsmore responsive to standard anticancer

drug treatment. Thismeans, they say, thatthe drugs could becomepart of a combinedtreatment approachrather than a stand-alone therapy and as

part of personalized approaches inpatients whose cancers fit specific epigenetic and genetic profiles.The research was funded by a SPORE

grant for lung cancer from the NationalInstitutes of Health, the Hodson TrustFoundation, Entertainment IndustryFoundation, Lee Jeans, Samuel WaxmanCancer Research Foundation, Department ofDefense Breast Cancer Research Program,Huntsman Cancer Foundation, and theCindy Rosencrans Fund for Triple NegativeBreast Cancer Research. All of the studieshave been accelerated by funding from theStand Up to Cancer (SU2C) project in part-nership with the American Association ofCancer Research (AACR). •

Eberhart

ON THE WEB

Rudin



When does the new Bayview clinicopen and what can patients expect?My plan is to take the Kimmel CancerCenter’s Bayview program from a com-munity hospital to a fully participating aca-demic arm of Johns Hopkins. We expectthe clinical areas to open in the Spring of2013. They will include a medical oncologytreatment area overlooking a beautiful garden with 22 infusion chairs and privateexam rooms, and a radiation oncologytreatment area with two linear accelera-

tors. We will have a multidisciplinary lungcancer clinic to bring together for patients,in one clinic, all of the specialties involvedin the diagnosis and treatment of lung cancer. What makes our clinic particularlyunique is its focus on cancer prevention inaddition to cancer treatment.

What is your strategy for cancer prevention?The Kimmel Cancer Center Bayview cam-pus will have a dedicated center for cancer

prevention to balance the need to take careof patients with established cancers withan effort to identify and help people at risk.There are tens of millions of Americanswho are at permanent increased risk ofdeveloping lung cancer because of a prioror current history of smoking. Screeningfor early lung cancer using low-dose spiralCT scans save lives, and we plan to providethis screening for people with a history ofsmoking, but we are also taking it a stepfurther and planning interventions forpeople with premalignant nodules. Nodules (small abnormal spots on the

lung) are identified in about 30 percent ofheavy smokers who have spiral CT scans.Lung nodules are quite common, particu-larly in smokers, but they are not alwayscancer. We have developed a nodule clinicin collaboration with the PulmonologyDepartment to monitor and manage peoplewith nodules discovered through spiralCT. We will develop protocols and testprevention strategies that we hope willkeep nodules from progressing to lungcancer. The Kimmel Cancer CenterBayview team will be among the very firstin the world to use screening as a researchtool. With our Center’s depth of expertisein the genetic and epigenetic causes of can-cer, we can make inroads in preventionthat are not being done anywhere else. Wewill take an at-risk population and person-alize lung cancer risk assessment and pre-vention. People with precancerous lesionswill have the opportunity to participate inintervention trials that target molecularand cellular changes that this researchshows can lead to lung cancer in futureyears with the aim of reversing the process.

Does this work increase our understanding of lung cancer?Smoking is the leading cause of lung can-cer. By bringing these people in to theHopkins system, we will be able to betterunderstand tobacco exposure and lungcancer risk, genetic features, and familyhistory. We can begin to make progressby studying and evaluating treatmentsthat target the very earliest, premalignantchanges that lead to lung cancer—take outa cancer before it actually is a cancer. Ithink we have the opportunity to makeunprecedented strides against lung cancer.

MEET PHIL DENNISTHE KIMMEL CANCER CENTER AT BAYVIEWPhillip Dennis, M.D., Ph.D., is the new Director of the Bayview Campus of theKimmel Cancer Center where he is creating a Thoracic Cancer Center ofExcellence. He is a seasoned clinician and investigator who, before coming tothe Kimmel Cancer Center, had served as director of the NCI/Navy OncologyClinic at the National Naval Medical Center and was a senior investigator atthe National Cancer Institute, where he was the recipient of the Alton OchsnerAward Relating Tobacco and Health. Dennis shared his vision for theBayview campus.


TransformingProstate Cancer

[ C O V E R S T O R Y ]

byValerie Matthews Mehl

DETECTION, DIAGNOSIS AND TREATMENT

PROSTATE CANCER IS AN ICONOCLASTAMONG CANCERS. It is at odds with what expertsknow to be the optimal approach for most cancers: Find itearly and treat it early. Prostate cancer is different. It may beone of the few cancers humans can live with. It is most oftenslow growing, and even late-stage cancers can many timesbe held in check for years. On the other hand, it is a cancerthat kills many men. It is the second leading cause of cancerdeath for men. The challenge, then, is deciphering the “good”prostate cancer from the “bad.” As a result, it is a model forpersonalized cancer medicine as Johns Hopkins urologists andcancer scientists and clinicians lead the way, using the mostadvanced science and technology to redefine for the world who to screen, who to treat, and who to safely leave alone.


WHERE WE CAME FROM, WHERE WE ARE GOINGThe innovation that sets the Johns Hopkinsprostate cancer program apart can betraced, in part, to the inventive thinking ofPatrick Walsh and Donald Coffey. Theyset the standard—challenging cliniciansand investigators to think beyond the sta-tus quo; beyond what is adequate to whatis extraordinary. Walsh developed ananatomical, nerve-sparing approach tosurgery that, for the first time, cut out andcured prostate cancer without causingdevastating side effects for men. Patientsthe world over traveled to Johns Hopkinsto have Walsh’s surgery, and urologists-in-training sought to come to Johns Hopkinsto learn the pioneering technique. Today, it remains the most common surgery performed at Johns Hopkins.

Forward thinking, Walsh compiled anextensive database of thousands ofpatients and followed them for 30 years.What he and others learned from thesemen became the laboratory fodder for thebespectacled inquisitor Donald Coffeywho began exploring the basic biology ofprostate cancer and provided some of thefirst insights to the subtle and uniquevariations of cancer DNA. Like Walsh,he shared what he learned. One of JohnsHopkins School of Medicine’s first tripleprofessors, Coffee is the consummateteacher, inspiring generations ofresearchers to not only look for answersbut to ask questions that had never beforebeen asked. Those who studied under Walsh and

Coffey became leaders in prostate cancertreatment and research at Johns Hopkins

and around the world. Walsh, a clinician,and Coffey, a basic scientist, embodied thebench-to-bedside collaborations that arethe hallmark of Johns Hopkins medicineand provided strong roots for a prostatecancer program. This is, in many ways, the golden age.

Generations of clinicians and investigatorsprovide incredible depth to the prostatecancer program much like grandparentsdo for a family. Today, under the leader-ship of Kimmel Cancer Center DirectorWilliam Nelson, Brady UrologicalInstitute Director Alan Partin, andRadiation Oncology and MolecularRadiation Sciences Director TheodoreDeWeese, Johns Hopkins experts, from awide range of disciplines, are on the fore-front poised to transform how prostatecancer is detected, diagnosed, and treated.

[ C O V E R S T O R Y ]


Donald Coffey trainees have gone onto become titans in cancer discovery.Among them is Kimmel Cancer CenterDirector William Nelson, BradyUrological Institute Director Alan Partin,renowned cancer genetics pioneer BertVogelstein, and Prostate CancerFoundation President Jonathan Simons.

FIRST DO NO HARMThe purpose of early detection is to catcha cancer early so that it can be removed ordestroyed before it causes harm. It makessense for most cancers. The problem withdetecting prostate cancer early, however,is that the diagnostic procedures andtreatments can sometimes, particularly inolder men, cause more harm than the dis-ease itself. PSA (Prostate Specific Antigen), the

test that makes the early detection ofprostate cancer possible, is at the center ofthe dilemma. Recently, the United StatesPreventive Task Force recommendedagainst routine PSA testing for earlydetection claiming the harms outweighedthe benefits. Their announcement gainedwidespread attention, but the truth is,experts at Johns Hopkins had beenevaluating the test and changing prostatecancer screening and treatment longbefore the U.S. Preventive Task Forceweighed in. “We’ve known for a long time that

there is a lot of harm that can potentiallycome with PSA testing,” says, urologistH. Ballentine Carter who has studied andevaluated the test in large populations ofmen for more than 20 years. Carter andother Johns Hopkins prostate cancerexperts say that PSA is not inherently abad test as it has been characterized inrecent headlines. The problem, they say,is not so much with the PSA test, butinstead how the test is used.Before the Prostate Specific Antigen

test, or PSA as it is now commonlyknown, hit the market in the late 1980s,prostate cancer was essentially anuntreatable disease. There was nomethod for finding the cancer, and menwent to the doctor only after they beganexperiencing symptoms, such as troubleurinating or blood in their urine. By thattime, the cancer was already welladvanced, and it could not be cured.Surgery was used primarily to relievesymptoms, such as bladder obstructions

PERSONALIZEDCANCER SCREENINGThe numbers are staggering. Each year20 million men get screened with PSA.Many of them undergo unnecessarybiopsies, suffer complications such asinfection and bleeding, and still othershave surgery, radiation treatment, hor-monal therapies, and drug treatments thathave unpleasant side effects. Out of all ofthese men, less than one-third of 1 percentwill die from the disease. “It’s clear thatfor many men, the benefits may be smalland the harms significant,” says healthpolicy expert and Maryland CigaretteRestitution Fund supported investigatorCraig Pollack. The challenge is figuringout from among the masses, which menwill benefit from screening and whichones will not. Confusion abounds, says Pollack. Ask

patients why they get screened, and theysay it is because their doctor recommendedit. Ask doctors why they recommendscreening, and they say their patientsexpect it. While Pollack finds that mostprimary care providers he has surveyedrecognize the issues surrounding routinePSA screening, they are unsure abouthow to explain it to their patients. “There are clearly some mispercep-

tions,” Pollack says, “and since the major-ity of screening occurs in the community,we need to provide them with a decision-

(Left to right)Schaeffer, Partinand Carter

caused by tumors, and it often left menincontinent and impotent. For a man withprostate cancer, it seemed that if the cancer did not claim his life, it certainlywould claim his quality of life.It is no surprise, then, that when a

test was developed that could detect thecancer early, before there were anysymptoms, it was going to be used.Imagine, Carter says, if such a testexisted for pancreas or lung cancer.Overdetection or not, people would bestanding in line to get the test.With no science to guide when

prostate cancer screening should beginand how often it should be done, howev-er, the nation, overzealously embarked ona practice of overscreening, overdetecting,and overtreating the cancer with freescreenings and “awareness” campaignsthat helped fuel the trend.The result was a dramatic increase in

prostate cancer incidence, and mostexperts agreed that many of the cancersdetected would have never caused anyharm. Doctors were finding a lot ofprostate cancers, but many of them, JohnsHopkins scientists found, would never bea problem. “Now,” Carter says, “we mustmove to a more measured approach.”He and other Johns Hopkins prostate

cancer experts have put medical scienceback in the equation and using soundresearch to determine how best to screenfor prostate cancer and how to tease outthe prostate cancers that are likely to killfrom those less aggressive forms that maynot require treatment.


making tool that can help them improvetheir practice.”Such a tool, a novel computer-based

system, which can be integrated withpatients’ electronic medical records, wasdeveloped by Carter, Pollack, cancerprevention and control expert ElizabethPlatz, and other Johns Hopkins cancerand public health experts. It will be pilotedin Johns Hopkins Community Physiciansoffices throughout Maryland. They hopeit will help primary care providers dis-cuss prostate cancer screening with theirpatients and direct PSA to men who willbenefit and away from those who will not. The decision-making tool takes into

account age and personal medical history,along with previous PSA test results andserves as an interactive guide for physi-cians to use when talking to patientsabout prostate cancer screening. Pollackand his colleagues found that while mostphysicians said they took age and lifeexpectancy into account when deciding toorder PSA screening, many also said theyhad a hard time estimating life expectancyin their patients and welcomed help inthis area.Screening is not one size fits all, says

Carter. While Pollack acknowledges thatmaking the shift from a populationapproach, in which everyone is screened,to an individualized approach, directed toonly those who good research tells us willbenefit, can be challenging. Men who arenot recommended for screening, particu-larly if they have been screened in thepast, may be concerned, and doctors mayworry they could miss a cancer. However,Pollack says there is conclusive evidencethat annual screening is not necessary foreveryone. “An individualized approach

just makes sense,” he says. “Our goal is todemonstrate that a personalized approachresults in better care and fewer complica-tions at a lower cost, and that is good foreveryone,” says Pollack. “ If a man aged 40 to 75 comes in for an

appointment, rather than routinely offer-

ing screening, doctors will instead beprompted to discuss the potential benefitsand risk of PSA with him. The toolincludes talking points to help guide doc-tors to speak to their patients about thepotential risks and benefits of PSAscreening. Doctors will also be promptedto explain the potential harms and bene-

fits of treatment.“The goal is to reduce screening, and

ultimately treatment, in people we know,with certainty, will not benefit, andincrease it among people who will,”Carter says. Men have grown to expectPSA screening to be part of their annual

physical. This tool helps address misper-ceptions about screening and facilitatesdiscussions that will help doctors andpatients make more informed decisions.Carter has conducted large populationstudies involving thousands of men, andthe data overwhelmingly show that menover age 75 are more likely to die withprostate cancer than of it, particularly ifthey have other more pressing healthproblems. As a result, these men will notbenefit from PSA, and Carter says doctorsshould explain that to them. KimmelCancer Center director and prostate cancer expert William Nelson frames itthis way, “I tell men who are over 75 andconsidering routine screening, ‘You don’tneed it. You’ve won. Prostate cancer isnot going to be a problem for you.’” If the doctor and patient determine

screening would be beneficial, the toolalso provides recommendations for whenand how often to rescreen.With all of the confusion, clinician

Bill Nelson

IT’S INFLAMMATORYTHERE IS A compelling body of evidence that links inflamma-tion to prostate cancer. It’s not acute inflammation, the kindthat occurs briefly when tissue is injured, but chronic inflam-mation—an ongoing assault and stress to tissue that contin-ues day after day without end. Population studies by ElizabethPlatz and team have found that men with chronic inflammationhave a higher risk of developing aggressive forms of prostatecancer. William Nelson led a research team that found thatenvironmental exposures, such as eating charbroiled meat,can cause inflammation inside the prostate gland and poten-tially influence the early stages of prostate cancer. Now,investigators are comparing normal prostate tissue andprostate cancers to better understand the extent of prostateinflammation and how it influences cancer development andprogression. They will also identify the specific types ofimmune cells that are triggered by an inflamed prostate toimprove and develop immune-based treatment approaches. •

THE GOAL IS TO REDUCE SCREENING,AND ULTIMATELY TREATMENT, IN PEOPLEWE KNOW, WITH CERTAINTY, WILL NOTBENEFIT, AND INCREASE IT AMONG PEOPLE WHO WILL.


Michael Carducci wants to be sure thatmen who have prostate cancer understandthat the PSA controversy only involvesscreening. PSA, he says, remains a vitaltool in monitoring men who have alreadybeen diagnosed and in determining ifthere is a medical problem in men whoare experiencing symptoms. “If you are aguy who is up five times a night going tothe bathroom, you have blood in yoururine, or erectile dysfunction. This is nolonger screening. This is diagnosis,” saysCarducci. “It is important that menunderstand the difference.”

TO TREAT OR NOT TO TREAT

SOME OF The greatest potential of personalized medicine is inusing our new knowledge aboutthe biology of cancer to get the

right treatments to the right patients.Sometimes the right treatment may be notreatment. One important way to reduce harm to

men is to individualize the managementof prostate cancer. PSA alone is notresponsible for the adverse affects menhave suffered; it has been what doctorshave done with PSA—mainly overtreat-ing the disease. When a man is diagnosedwith cancer, Carter says, it is importantfor him to know that invasive treatmentsare not the only option.Treatments for prostate cancer can

include the surgical removal of theprostate, radiation, hormonal therapies,and chemotherapy. Each of these has thepotential to cause serious problems, suchas erectile dysfunction, impotence, andurinary incontinence or bowel damage.For many men, treatment is clearly thebest option, and our prostate cancer clini-cians are among the best in the world.Johns Hopkins clinicians have pioneeredsurgical, radiation, and drug remedies forthe disease, but they have also been on theforefront of a nontreatment approach. It iscalled active surveillance—active beingthe key word.Carter, although one of the world’s

leading prostate cancer surgeons, believesthat putting the scalpel aside is sometimesthe best tactic for men who are diagnosedwith a low-grade form of the disease. Theapproach has been the focus of researchin the Brady Urological Institute at JohnsHopkins since 1995. Data gleaned fromseveral large studies unequivocally

showed that many men with low-gradedisease would never be harmed by theircancer but could be, and all too often are,harmed by treatment. “The majority ofmen diagnosed with prostate cancer eachyear are over 65 and have a low risk ofdying of their disease if treatment isdeferred,” says Carter. “Yet, more than90 percent of these men, including 80 per-cent who are over age 75, are likely tochoose some form of treatment. Activesurveillance addresses excessive treat-

ment of milder stages of prostate cancer,especially in seniors.”About 40 percent of men are diagnosed

with low-risk disease, and for a signifi-cant number of them, active surveillanceoffers a way to very carefully monitortheir cancer and give them the option todelay treatment as long as it does notprogress. Many of these men will neverrequire treatment, but if they do, carefulsurveillance allows the growing cancer tobe spotted and treated while it is still cur-able. A National Cancer Institute (NCI)model that uses computer simulation todetermine patient outcomes evaluated allof Carter’s active surveillance data andcompared it to data from men who wouldhave qualified for active surveillance butchose surgery. In a worst-case scenario,the NCI model found that over a 15-yearperiod, men who chose active surveillancestood to gain an average of seven addition-al years of not being treated, and at themost, risked losing three months of life. Pennsylvania businessman Alex

Cameron was one of the first participantsin active surveillance. Cameron was inhis late 50s in 1999 when he was diag-nosed with prostate cancer and beganexploring options including hormonetherapy, brachytherapy, and surgery. Inhis research, he also learned of Carter’sactive surveillance approach and sched-uled an appointment. He admits that witha wife, three daughters, and eight grand-children to live for, the idea of leaving thecancer alone was somewhat troubling to

him and his loved ones. Cameron’sprostate cancer fit the parameters foractive surveillance. He had a low Gleasonscore and his cancer was very slow grow-ing. “Active surveillance sounded like awin-win good thing,” says Cameron. Hesays regular biopsies done under localanesthesia to monitor his cancer were aminor inconvenience in exchange for hisongoing and treatment-free health. Hesays he was also comforted by the knowl-edge that five of the world’s best prostate

cancer pathologists were reviewing hisbiopsy samples. Today, at age 71,Cameron remains active and healthy andconfident that he made the right decision.“For any guy in my situation,” he says,“active surveillance is the way to go.” Cameron is among the more than 1,000

men who have participated in active sur-veillance since Johns Hopkins beganoffering it 16 years ago, and there are currently about 600 men enrolled. Theaverage participant is 67 or older. Thisoption, Carter says, is for men who arelikely to live out their natural lives withoutbeing harmed by prostate cancer. Inother words, prostate cancer is not goingto kill them. The men have a PSA testand rectal exam every six months as wellas an annual biopsy to carefully monitortheir cancer. More recently, Carter hasadded MRI (magnetic resonance imaging)to surveillance. “We know that there ispotential to underestimate the extent ofdisease in some men, and MRI helps usmake sure we haven’t missed anything,”says Carter. “A recent study showed thatwhen MRI found there was no cancerthere, there was really no cancer there.” For many years, Johns Hopkins was

the only cancer center to offer active sur-veillance. This is, in part, because med-ical reimbursement is a fee-for-servicesystem that favors procedures. JohnsHopkins urologists, arguably the best

FOR MORE ON PROSTATE CANCER


“I TELL MEN WHO ARE OVER 75 ANDCONSIDERING ROUTINE SCREENING,‘YOU DON’T NEED IT. YOU’VE WON.PROSTATE CANCER IS NOT GOING TOBE A PROBLEM FOR YOU.’”


trained in the world, were the only oneswilling to explore the possibility of a bet-ter option for some patients. Endorsement of active surveillance by

the Prostate Cancer Foundation andheightened concerns about overtreatmentstemming from the U.S. Preventive TaskForce’s recommendation, is now bringingthis “no-treatment” treatment new consideration. The Prostate Cancer Foundation is

working to provide patients more assur-ance and has established the NationalProactive Surveillance Network, a Web-based system (NPSN.net) that provideseducation about active surveillance andhelps patients find participating doctors.Soon, patients and physicians will be ableto securely access the system to enter,review, and track their own data. Menparticipating in active surveillance wouldbe able to enter all of their PSA data andtrack their personal results to see wherethey fall in respect to other participants.

MOLECULAR REASSURANCEStill, many men, upon learning they have prostate cancer, are uncomfortableleaving the cancer untreated. “They needstronger, quantifiable reassurance thattheir cancer won’t hurt them, and we don’thave the ability to give them that rightnow,” says prostate cancer researcherSrinivasan Yegnasubramanian. Hebelieves if physicians were able to removeany doubt, it might change minds and significantly improve outcomes for men.He is working to create an accurate testthat could be applied to blood or urineand provide clear biological evidence todistinguish aggressive prostate cancersfrom the slow-growing type, which couldbe left alone.A Gleason score is an excellent barom-

eter of aggressiveness, but it is only asgood as the sample, he says. In men whohave a prostatectomy, it is very tellingbecause pathologists have the entireprostate to examine. When a tumor issampled through a biopsy, though tech-nology has greatly improved, it is stillpossible to miss critical areas of a tumorthat could be the key to distinguishingharmless cancers from dangerous ones.Removing this uncertainty is at the core of Yegnasubramanian’s research.His test is based on chemical alter-

ations to specific regions of genes. They

occur without mutating DNA but canhave the same effect as mutations andsilence the function of important tumorsuppressor genes. These changes, knownas epigenetic alterations, are a signaturefor cancer and when they are seen or

begin to increase, they can alert doctors toa growing cancer. Moreover, they are verycommon in prostate cancer. “Epigeneticalterations can occur more frequently andconsistently than mutations in prostatecancer,” says Yegnasubramanian.

Yegnasubramanian


Not only do these alterations serve assignatures for cancer, they are also poten-tial therapeutic targets. Unlike mutations,in epigenetic alterations, affected genesare not missing. Instead, they aresilenced by changes in the chemical envi-ronment, so researchers have the oppor-tunity to use drugs to revert genes back tonormal function. Epigenetic signaturescould be used to distinguish indolentprostate cancers from aggressive ones,monitor cancers for progression andrecurrence, and to determine whethertreatments are working.In recent years, the pace of these dis-

coveries has greatly accelerated because ofa new technology known as next generationsequencing. This powerful technology hasthe ability to rapidly and simultaneouslysequence millions to billions of DNAmolecules. As a result, cancer researchthat used to take decades can now becompleted in weeks. Yegnasubramanianis the director of the Kimmel CancerCenter’s Next Generation SequencingCenter, located in the David H. KochCancer Research Building. He and his team are using this technol-

ogy, in conjunction with new techniquesthey have developed, to profile prostatecancers and identify a panel of epigeneticmarkers unique to prostate cancers withhigh Gleason scores and another to charac-terize cancers with low Gleason scores.Once they identify the specific markersthat brand both aggressive cancers andslow growing ones, they can adapt thetechnology to find them in blood and urine.“If there is a question we can ask

where genomic information can helpinform who should get a particular treat-ment and who should be monitored, Ithink we can go after it,” saysYegnasubramanian. “The prostate cancerprogram has one of the best teams onearth to define and tackle these ques-tions.” Though many centers are think-ing about these problems, he says JohnsHopkins is uniquely positioned because ofits strength in translational medicine tomake progress. “We have equal strengthin the clinic and the laboratory,” he says.“This is a major asset that is rarely foundin other centers doing genome research.Some have the research component butdo not have the clinical strength we havehere. Having both, allows us to make the critical connection between what we

find in the laboratory and what will trulybenefit patients.”Yegnasubramanian also is collaborating

with Kenneth Kinzler, one of the world’sleading cancer genetics experts, StephenBaylin, a foremost epigenetics expert, and nationally known prostate cancerinvestigators Michael Carducci and MarioEisenberger to better understand how differences in the prostate cancer genomeand epigenome have an impact on treat-ment outcomes. His research will helpphysicians make the right treatment decisions for each individual prostate cancer patient. In prostate cancer that recurs and

spreads after treatment, the first line ofapproach is hormone (androgen) suppres-sion therapy—in essence cutting off thesupply of hormones that are believed tobe fueling the cancer. At this stage, mostmen will survive about four years.However, our investigators have foundthat there are extremes in patient survivalthat could provide important new cluesabout the disease. Some men progressrapidly and may die within the first yearof their recurrence, but others appear tobe cured by the hormone suppressiontherapy, living for years without any signof cancer recurrence. Yegnasubramanianand team believe the reasons for these dif-ferences are hidden within the genomeand epigenome of prostate cancer, andthey are hoping to use the power of nextgeneration sequencing to uncover the biological differences.

What is different about the cancerDNA of long-term survivors versus thosemen who have a very rapid progression?The answer would allow clinicians todirect more intensive therapies to menwhose cancer DNA predestines them tobe less responsive to standard treatmentsand give less therapy, or stop treatmentaltogether, in men whose cancer DNApoints to long-term remission. What theylearn about the extremes of treatmentresponses should also help all men with

prostate cancer by shedding new light onother mechanisms that could be targetedin treatment. What the investigatorsuncover about the genetic and epigeneticbasis of extremes of therapeutic responsein prostate cancer will likely reveal similar information about other cancers.

PROVING A NEGATIVE

THE OLD ADAGE, “You can’t provea negative,” is a dilemma at thecore of creating better screening

and diagnostic tests for prostate cancerthat limit the need for invasive procedures.How do we use scientific discoveries toprove the absence of cancer with the same certainty as we prove the existenceof cancer?Despite its problems, Brady Urological

Institute Director Alan Partin and otherprostate cancer experts say PSA is aninvaluable tool in helping monitor menwho have already been diagnosed and,even with its limitations, remains useful inthe diagnosis of prostate cancer. With a lit-tle help, Partin says it could be even better. Throughout his career, Partin collected

blood, urine and serum samples from his patients and created the world’slargest prostate biorepository. It greatlyadvanced the understanding of prostatecancer and has been critical in his work to develop biomarker tests that could aug-ment PSA. The tests, he says, could helpdiagnose prostate cancer without expos-ing men to repeated biopsies. PSA detectscancer but it also detects a lot of other

things. “We need a test that when it’snegative, we know the patient is OK.When it’s positive, we want to be confi-dent that it’s truly positive. We don’twant to continue doing four biopsies tofind the one cancer we’re looking for,” saysPartin, who is the David Hall McConnellProfessor of Urology.

SEE VIDEOS ON PROSTATE CANCER


“IF THERE IS A QUESTION WE CAN ASKWHERE GENOMIC INFORMATION CAN HELPINFORM WHO SHOULD GET A PARTICULARTREATMENT AND WHO SHOULD BE MONITORED, I THINK WE CAN GO AFTER IT.


A positive PSA means only that a mancould have prostate cancer. Currently,the only way to know for sure is to biopsythe cancer, a process in which a needle isguided by ultrasound, and more recentlyMRI and other imaging technologies,through the rectum into the tumor.While Johns Hopkins cancer researchersand engineers have led the way in devel-oping new technologies that makeprostate tumor biopsies remarkably pre-cise and safe, many men still undergorepeat biopsies to confirm or disprove acancer. Each biopsy carries a risk ofbleeding and infection. Partin believes anew urine test based on a genetic discov-ery by Brady Institute laboratory scientistWilliam Isaacs may help dispel some ofthe uncertainty and alleviate the need formultiple biopsies.

Unlike PSA, this new gene-basedurine test, called PCA3, only detectsprostate cancer, but it too has its limita-tions. While PCA3 outshines PSA interms of its specificity to prostate cancer,it is not as sensitive, so it has the potentialto miss cancers. PSA, on the other hand,is very sensitive—quite good at picking upabnormalities in the prostate—including(but not limited to) cancer. Combined, thetwo tests compensate for the other’sshortcomings and, as a result, have thepotential to very accurately detect cancer.If a man has an elevated PSA, but a biop-sy did not reveal cancer, Partin says thePCA3 test could potentially serve as thefinal word. “If a PCA3 is negative, youcan trust that the patient probably doesnot have prostate cancer. If it is positive,then he probably does,” Partin explains.“It adds another piece of information tohelp us better and more safely diagnoseprostate cancer.”Partin also is working on a test called

AccuPSA to monitor prostate cancerpatients following surgery for what is

referred to as biochemical recurrence.The test uses new nanotechnologyapproaches to measure PSA values 1,000times lower than a standard PSA test. Arising PSA without any visual tumors isconsidered a biochemical recurrence, andwarns clinicians that prostate cancer cellsmay remain in the prostate and increasesthe likelihood that the cancer will ulti-mately return and spread. Partin and team studied blood samples

from 31 men who had undetectable PSA,using the standard test, for five years afterprostatectomy. One-third of the men laterbegan to have a rising PSA, and whenPartin used AccuPSA on the blood sam-ples, he found that the one-third of menwith biochemical recurrence had a smallbut measurable rise in their PSA justthree months after surgery. In the other

men, 75 percent had AccuPSA levelslower than the men who recurred. Thesmall study allowed Partin and team todetermine a threshold for AccuPSA thatcould help them distinguish, within a fewmonths after surgery, men whose cancerhas been entirely eliminated with surgeryfrom those who may have had someremaining cancers cells that could putthem at risk for cancer recurrence in theimmediate years after surgery.Identifying which men will have can-

cers that are likely to be cured with stan-dard treatments and those men who havecancers destined to return and spread isessential to the management of prostatecancer, says Partin.

SEPARATING THE “GOOD” FROM THE “BAD”The complexities of managing prostatecancer go beyond the PSA controversy. Prostate cancer experts have gotten

extremely adept at separating aggressivecancers from nonaggressive cancers. TheGleason score, first established in the

1950s and later refined by Johns Hopkinspathologist Jonathan Epstein, ranks thenature of the prostate cancer on a scale of six to ten. Gleason six represents alower- risk cancer; seven through 10means the cancer is more dangerous. In short, the lower the number is, the better. Evaluated in conjunction withPSA (Prostate Specific Antigen) tests,biopsy results, and the size of the tumor,our experts say it does a good job guidingtreatment.

ATARGETED RADIATIONTHERAPYA NEW FORM OF targeted radiationtherapy, known as proton beam thera-py, very precisely zeroes in on tumors,increasing the damage to cancer cells,while minimizing radiation exposureto healthy tissue and organs. Its precision and safety has improvedradiation treatment and become thestandard of care for pediatric cancers,tumors of the brain, spine and eye,and cancers of the lung, head andneck, and bone (sarcoma). TheKimmel Cancer Center is currentlydeveloping plans for a proton beamfacility on its Washington, D.C., campus to provide care for patientswith these types of cancers and alsowill be one of the few centers embark-ing on evidence-based research todetermine other cancers best treatedby proton beam therapy.There is growing concern among

prostate cancer clinicians and scien-tists because the most commonly pro-ton beam-treated cancer is prostatecancer, and there are currently noresearch studies or findings to supportit. Kimmel Cancer Center DirectorWilliam Nelson and RadiationOncology Director Ted DeWeese, bothprostate cancer experts, are among theconcerned, and they are committed togathering the needed research-basedevidence to prove, or disprove, its ben-efit. One of the first research projectsat the Kimmel Cancer Center protonbeam facility will be the importantbasic science and clinical studies thatwill help resolve the scientific contro-versy surrounding the use of protonbeam therapy for prostate cancer. •

IDENTIFYING WHICH MEN WILL HAVECANCERS THAT ARE LIKELY TO BECURED WITH STANDARD TREATMENTSAND THOSE MEN WHO HAVE CANCERSDESTINED TO RETURN AND SPREAD ISESSENTIAL TO THE MANAGEMENT OFPROSTATE CANCER.


As one of Hopkins busy prostate can-cer surgeons at Johns Hopkins, EdwardSchaeffer has observed first hand thatwhile many of his patients are cured withsurgery, some of them inexplicably havetheir cancers return. In his laboratory, he is working on ways to identify thesepatients and to develop new treatments to prevent the cancer’s return.To decipher clues about the abnormal

cell growth that leads to prostate cancergrowth and spread, Schaeffer identifiedand focuses on a group of genes that regu-lates and controls normal prostate devel-opment. He postulated and subsequentlyshowed that genes that control the move-ment and invasion of prostate cells duringnormal prostate development, becomereactivated in prostate cancers.Schaeffer’s work has not yet revealed thetriggers to turn these invasive genes backon, but he has found that the molecularprocess is linked to the most aggressiveprostate cancers. This promising findingallows him to not only pinpoint thosepatients whose cancers are destined toreturn after surgery, but it also reveals apotential new target for treatment. Schaeffer’s laboratory team, led by

Paula Hurley, is particularly interested ina gene known as SPARCL1, which canaccurately predict whether a seeminglylocalized tumor will return and spreadwithin a few years after surgery. The nor-mal prostate has high levels of SPARCL1expression, which holds cells in check,preventing them from migrating andmoving around. Low levels of SPARCL1allow cells to move well, serving as a bio-logical red flag that the cancer will returnwith a vengeance. Currently, Gleason Score is used to

identify more aggressive prostate cancers.For example 30 percent or more ofpatients with a Gleason Score of seven orhigher are at highest risk of having theircancers return. Unfortunately, there iscurrently no way to differentiate thepatients who are cured with surgery fromthose whose cancer will recur. MeasuringSPARCL1 expression at the time of sur-gery seems to provide the answer. Inaddition, Schaeffer’s research indicatesthat SPARCL1 could also play a role inpredicting tumor recurrence in a numberof other tumors, including bladder,breast, colon, rectum, tongue, lung, skin,and ovarian cancers.

Schaeffer is now working to decipherthe specific mechanism that controls thegene in hopes of developing a treatmentthat can reset SPARCL1 to normal andprevent cancers from returning.

THE CASE FOR OPEN AND CLOSED

THE DA VINCI robotic surgical sys-tem has made minimally invasivesurgery a household word and has

become a favorite marketing tool of com-munity hospitals around the country. The da Vinci system boasts smaller

incisions, less pain, shorter hospital stays,and shorter recovery time for patients. In certain instances, this is true. Forprostatectomy, however, not everyoneagrees. Prostate surgeons—like AlanPartin, H. Ballentine Carter, EdwardSchaeffer, and the many other urologists

who learned how to do prostatectomiesby training under its pioneer PatrickWalsh, the undisputed paragon for how itshould be done—do not need the assis-tance of da Vinci. On the other hand,robots can be quite helpful and sometimesmake it possible for surgeons who do nothave the skills to perform a Walsh-styleopen procedure to perform prostatectomies. When it comes to prostate cancer, men

may have a difficult time distinguishinggood marketing from good medicine.Patients hear advertisements about onemachine or another, and they think iftheir doctor does not use it, he is not practicing good medicine, warns JohnWong, a Kimmel Cancer Center medicalphysicist who has invented several cancer-related devices. Many claims, hesays, are made with no scientific evidenceto back them up.

CHOLESTEROL DRUGSGOOD FOR HEART DISEASE AND PROSTATE CANCERPOPULATION STUDIES AT JOHNS HOPKINS have shown that men on choles-terol-lowering drugs known as statins have a greatly decreased risk of developingadvanced prostate cancer. Physician and scientist Phuoc Tran has gone back to thelaboratory to figure out why. He suspects that these drugs block the activity of animportant cancer-growth-promoting gene known as c-myc, and he proved in laboratorystudies that high-dose statins, in fact, reduce c-myc activity. Now Tran, a radiationoncologist and expert on the c-myc oncogene, has initiated a clinical trial in collabora-tion with urologist Edward Schaeffer to verify in prostate cancer patients what heobserved in the laboratory. If he confirms his findings, it could open the door to treat-ment strategies that could improve surgery or radiation therapy outcomes. Similarly,statin-based prevention approaches could lock prostate cancer in a nonthreateningstage and potentially stop it from occurring at all. •

Tran


Partin agrees, saying that JohnsHopkins always evaluates new approachesfrom an evidence-based scientific stand-point. “We were using the da Vinci robotlong before it was famous,” says Partin.“But, we take marketing and profits out of the equation and look at what reallyworks the best for patients.”Investigators in the Johns Hopkins

Center for Computer-Integrated SurgicalSystems helped develop some of the tech-nology used in the da Vinci system, whichemploys robotics, sensors, imagingdevices, and guidance systems to interfaceand assist surgeons when operating.Brady Urologist and biomedical engineerMohamad Allaf works with these scien-tists and is director of minimally invasiveand urological robotic surgery. JohnsHopkins was one of the first medical institutions to integrate robotics into uro-logic surgery, and Allaf is considered oneof the world’s leading experts. He travelsaround the globe demonstrating and train-ing other surgeons in robotic prostatectomy,nephrectomy (kidney) and other urologicaloperations. Like the other Brady surgeons,Allaf is as skilled at open procedures as he is at robotic approaches, but with thecontinuing demand from patients for minimally invasive procedures and hiswork innovating the next generation ofrobotics in medicine, it is his focus. In terms of prostatectomy, Partin says

it’s a draw. Studies show that open procedures and robotic procedures, when performed by trained surgeons, are equally good and there is really notmuch difference in pain or recovery.

Training is key. Patients need tounderstand that that the robot is not asimportant as who is operating the robot,says Schaeffer. Johns Hopkins urologistsare probably the best in the world at bothopen procedures and robot-assisted sur-gery, he says. Patient demand supportsthis contention. Johns Hopkins urologistsare the most sought after, performing hundreds more prostatectomies than anyother hospital in the world. Their recordis stellar, getting all of the visible cancer 90 percent of time while also preservingsexual and urinary function. Schaeffersays he finds that some men prefer theminimally-invasive prostate surgeryapproach, so unless the tumor is large andbulky or has other characteristics thatdemand an open procedure be performed,he usually leaves the choice up to thepatient. This is where the skill of the JohnsHopkins urologists, experts at both typesof surgery, makes a difference. They arenot limited to one or the other, so they canselect the approach that is best suited toeach patient’s individual cancer.

HELPING PATIENTSMAKE THE RIGHT DECISIONJohns Hopkins prostate cancer expertshave pioneered therapies, diagnostic tests,imaging techniques and basic science dis-coveries. However, what Schaeffer and hisfellow Johns Hopkins urologists and oncol-ogists take the most pride in is providingpersonalized treatment plans for eachpatient, whether it is surgery, radiationtreatment, hormone therapy, active surveil-lance or a combination of these approaches.

NO SMOKEA GOOD REASON TO QUIT; A GOOD REASON TO DIETCORINNE JOSHU, the Martin D. AbeloffCancer Prevention and Control Scholar-in Training, was looking for straightfor-ward lifestyle remedies that coulddecrease the risk of recurrence in men

who had surgery forprostate cancer andwhose cancer had notspread. She found thatmen who were smokingone year after surgerydoubled their risk of

their prostate cancer coming back.Former smokers and nonsmokers hadno increased risk. Joshu says that smok-ing causes cell damage that triggers thegrowth of new cells to replace damagedcells. It’s possible that this process setsin motion genetic changes that facilitatethe return of the prostate cancer.Joshu also looked at weight change

from five years before surgery to oneyear after. She found men who gainedfive or more pounds (10 to 11 pounds onaverage), after surgery also doubledtheir risk of cancer recurrence whencompared to men who maintained theirweight. It didn’t matter if they werenormal weight or overweight to beginwith. It was the act of gaining weightthat seemed problematic. Joshu isworking with researchers to figure outwhy. “If you’re gaining weight, you arein the process of active growing.Perhaps this growth-promoting envi-ronment allows evasive tumor cells toset up shop and cause a cancer recur-rence down the road,” she says.With support from the Abeloff

Scholars program and the MarylandCigarette Restitution Fund, Joshu isinvestigating precisely how theselifestyle factors contribute to prostatecancer progression.“On a day-to-day basis, our bodies

are trying to fight the outside world,”explains investigator Michael Carducci,who is collaborating with Joshu on thestudy. “Internally things are gettingturned on to combat these exposures.The more you can limit these forces bynot smoking and maintaining a healthyweight and diet, the easier you make iton your body.” •Drake

Joshu


treatment best suited to each patient,”says Schaeffer. “People come to our clinicafter being told they need surgery and arerelieved to find out we can offer them analternative to surgery. By the same token,we have men who come to our clinicbecause they have been told they cannothave surgery, and we cure them,” he says.He recalls one patient, in particular. Hewas 47 years old and had been told hiscancer was incurable. He came to theprostate cancer clinic, where Schaefer and team worked out a plan that includedsurgery and radiation therapy. Thatpatient continues to do well today.Why can Johns Hopkins experts offer

patients treatments that other hospitalscannot? “The technical experience is better here than anywhere else in theworld,” says Schaeffer. “But just asimportant, we know how, when, and towhom to employ this expertise. This personalized approach is the essence ofthe Prostate Multi-D Clinic, and we do itbetter than just about anyone.”

SCIENCE, POPULATIONS AND PROSTATE CANCER

ELIZABETH PLATZ IS a populationscientist. She uses questionanaires,records, and biospecimens to

observe men—what they do and whatthey do not do—and applies what she seesto prostate cancer. For example, her land-mark study of nearly 5,600 men aged 55and over, found those with normal or lowserum cholesterol had a 60 percent lowerrisk of developing aggressive (high-grade)prostate cancer than men who had borderline and elevated levels. In an earlier study she observed that men whoused cholesterol-lowering drugs knownas statins had a decreased risk of develop-ing aggressive prostate cancer. There seemed to be a link—men with

lower cholesterol and men who used cholesterol-lowering drugs, improvedthere prognosis, decreasing their risk ofdeveloping a more aggressive form ofprostate cancer. To determine why shefinds the things she finds, Platz, theMartin D. Abeloff Scholar in CancerPrevention and Control, turns to her laboratory and clinical science colleaguesto unearth answers, and vice versa.Marion I. Knott Professor and Director

of the Kimmel Cancer Center WilliamNelson and investigator SrinivasanYegnasubramanian worked withresearcher Jun Liu, who has constructed arepository of more than 3,000 FDA-approved medicines, in hopes of identify-ing some commonly used noncancerdrugs that might work against prostatecancer. When they screened humanprostate cancer cells against the druglibrary, two of the top 15 hits were statindrugs. One was digoxin, an older drugthat, in the past, was commonly used totreat congestive heart failure. Scientists are looking for new ways to

contain the cost of drug discovery, anenterprise in which a billion dollars can bespent to bring one drug to market. Thepromise of most drugs, or lack thereof, isusually only realized after years of costlyresearch. As director of a cancer center,Nelson understands cancer researchershave to do better. He envisioned a two-stageapproach to see if what he, Yegnasubramanian,and Liu found in the laboratory studies ofprostate cancer cells would be supportedor refuted by what Platz observed in men.

Platz

Schaeffer, medical oncologist CharlesDrake, and radiation oncologist DannySong co-direct a clinic where patients from

around the world come tohave their prostate cancerscrutinized by leaders inthe field. Some men havelocalized disease and areuncertain about what isthe best treatment for

them. Others have more aggressive can-cers they have been told are not treatable.About-one quarter of the patients whocome to the clinic have a change in thegrade or stage of the cancer, once examinedby the Johns Hopkins team, which includeradiologists and pathologists, like JonathanEpstein, the world’s most sought afterprostate cancer pathology expert. Most ofthe time, patients get better news thanwhat they were initially told. By the end ofthe day, the crack team will have laid outfor them treatment options and plans.“We offer a service based on our

extensive experience that delivers the

Song

(continues on page 22)


Photography: Peter Howard

Damon SingsFormer Temptations member DAMON HARRIS

reflects on his 14-year battle with prostate cancer.

[ TRANSFORMING PROSTATE CANCER ]

byValerie Matthews Mehl


DAMON WAS DIAGNOSED

with advanced prostate can-cer in 1998 at just 47 yearsold, but he has since learnedfrom his doctors that this

slow growing cancer had probably startedforming 20 years earlier. At the time thephotos were taken, there were no symp-toms to alert him to the invisible geneticmiscues occurring within his body andgiving rise to the cancer cells. He wasunaware that as an African- Americanman with a family history of prostate can-cer, he was at increased risk for the dis-ease and at risk for developing it at ayounger age. His father died when Damonwas just 25. However, Damon did notrealize until he read the death certificatethat his father died from prostate cancer.“I saw my Dad die. I saw him suffer, buthe never talked about it,” says Damon. Itwas indicative of the time. “Black mendidn’t talk about prostate cancer,” he says. Flash forward 15 years, and perhaps

things are not that different. Damonrecalls living with symptoms for fiveyears before going to the doctor. Like hisfather before him, he suffered in silence.He convinced himself that the pain hewas experiencing was just a normal partof middle age. “I was stretching and put-ting cold compresses on my pelvis tryingto relieve the pain.” He was living in Philadelphia at the

time. He had spent the last decade touringinternationally as a solo artist and haddecided to relocate to Nevada to work witha singing group who was performing at ahotel in Reno. He enrolled at the Renocampus of the University of Nevada tocontinue his studies in music education.A few years later, the pain returned,

and now it was intolerable. Dr. CarolScott at the University’s Health Centerconvinced him that he needed a PSA testand prostate exam. The results were

unmistakable. Damon did not just haveprostate cancer; he had bad prostate can-cer. His biopsy and other tests revealedthat the cancer had already spread.

As a young man, he had dreamed ofliving in Reno. His plans did not includea diagnosis of prostate cancer. Withindays of his diagnosis, he went to the Renochapter of the American Caner Society(ACS) for what he calls his “crash coursein Cancer 101.” The local ACS directorasked Damon to be a coordinator andfacilitator for its Man-to-Man program, aneducation and support program for menwith prostate cancer. He spoke to manygroups. The black population in Renowas very small, so he was the only blackman in the room. “It was an eye-openingexperience for them and for me,” recallsDamon. “It was an unusual encounter forus all, but despite the obvious differences,we were brothers. The disease brought ustogether.”The ACS sent Damon around the

country to attend national conferencesand other prostate cancer events. His“crash course” also led him to anotherprostate cancer group. An internet search

turned up a patient-led advocacy groupcalled the National Prostate CancerCoalition (NPCC). The urologist Damonsaw in Nevada did not offer much hope,but a contact he made while attending thegroup’s annual meeting in Washington,D.C., did. Damon became friends withJudge Ralph Burnett, himself a newlydiagnosed prostate cancer patient and theorganization’s chairman at the time. Thejudge was a champion of increasedresearch funding and education for mendiagnosed with the disease. “He was gen-uinely concerned for me and told me Ineeded to see his doctor, Dr. Bill Nelson atJohns Hopkins,” says Damon Damon followed Judge Burnett’s

advice and made an appointment to seeDr. Nelson. Damon’s prostate cancer wastoo advanced to be cured with surgery,but hormone drug therapy could—anddid—keep it in check. The treatmentshave not been without their side effects,but he has been well enough to continueperforming. A highlight for him was per-formances last year at the Kimmel CancerCenter’s Cancer Survivor’s Day celebra-tion and Art of Healing Program. Hesang “We Shall Overcome,” and wasjoined by patients in a moving and spon-taneous display of courage and solidaritythat, while emotional for all who wit-nessed it, was probably only fully appre-ciated by those fighting cancer. “I wasmoved to ask patients to come stand withme because I could identify with whatthey were going through,” says Damon.“Though we all have different experiencesin fighting our cancer, we are also joinedtogether by a similar experience. I was theone on the stage singing, but my voicewas speaking for all of us.” For the first time, Damon has written,

arranged, and produced his own music.He recorded “You are My Woman” lastspring at Johns Hopkins Peabody

TODAY, WHEN DAMON HARRIS LOOKS AT OLD 1970s PHOTOGRAPHSof himself performing as a member of the vocal group the Temptations, he does not simply reminisce about his twenties and the heyday of his career. Instead he reflects at what the camera lens does not reveal. Beyond the spotlight andcelebrity, he marks the beginning of his battle with prostate cancer.


Institute accompanied by Peabody musi-cians. “People I have met through thisbattle and all that I have gone throughwith treatment, thinking I would neversing again, inspired me to record thissong,” says Damon. “Those experiencesgave me hope and purpose and a beliefthat my life was not over.” Damon says he also has drawn

inspiration from his old friend JudgeBurnett, who passed away in 2007, butnot before leaving a lasting mark. Underhis leadership, first as chairman and lateras a board member, the National ProstateCancer Coalition tripled its membership,and federal funding for prostate cancerresearch doubled. He was a staunch andvocal supporter of Johns Hopkins, lever-aging support from the Department ofDefense for the Johns Hopkins prostatecancer program and advocating for theKimmel Cancer Center’s National CancerInstitute SPORE (Specialized Programs ofResearch Excellence) grant for prostatecancer. Judge Burnett participated instudies that helped Johns Hopkins scien-tists begin to unravel the complex geneticchanges associated with prostate cancer. Judge Burnett asked Damon to help

the group reach out to black men who, asDamon now understood all too well, weremore likely to develop prostate cancer at ayounger age but less likely to getscreened. “Judge Burnett thought blackmen might feel more comfortable hearingfrom and talking to another black man,”says Damon. A deeply spiritual man,Damon began to find a Godly purpose inhis diagnosis. “Maybe I was being calledto do this. If I could use my experiencewith the Tempts and Motown as a plat-form to promote awareness, then I feellike something good came from mystruggle,” he says.Some black men have not been recep-

tive, he admits, but he refuses to give up.“My experience is not everyone’s experi-ence. Some people are intimidated. Somejust get tired of fighting the obstacles. Iwant to educate and arm all men, so theywill at least have the information theyneed to make decisions,” says Damon. “Iespecially want young African-Americanmen and the nation to understand thatthis is not just an ‘old man’s disease.’ I’mliving proof of that,” he says. Damonadmits that even if he knew there was aprostate cancer screening test or exam

when he began experiencing symptoms,he still would not have gone to the doctor.“Sadly, the thought of having a DRE [digi-tal rectal exam] is scarier for many menthan dying,” he says. “I’ve heard mensay, ‘I’ll die before I do that,’ and I want todo anything I can to make sure that does-n’t happen.” To help get his message out and pro-

vide support to African-American men,Damon has formed the Damon HarrisCancer Foundation and is developing anassociated website that links African-American men to African-American urol-ogists. It was an idea that came to himwhile attending a conference through theAmerican Cancer Society. A chancemeeting with acclaimed black urologistJanice Arnold made him think, “Maybesome black men would be more willing toget screening examinations if they couldgo to an African-American doctor. Thehistory of black people in America is suchthat some black men are understandablyreluctant to listen to white doctors. Thetrust is missing,” he says. “But, we can’tquit trying to get the message out.” Hisgoal is to make sure every man has anoption that works for him. If going to ablack doctor is more comfortable, hewants them to know where to find one.“Information is key,” says Damon.“People need to make their own decisions.The decision I made may not be the rightone for someone else, but I try to helpmake sure people at least have the facts,like ACS and the NPCC did for me.”

First and foremost, he hopes that shar-ing his story and providing connections todoctors will encourage men to discussprostate cancer with a doctor before theyhave symptoms. “Race is a sensitiveissue. The media are afraid to talk aboutthe problems of prostate cancer inAfrican-American men. There is a hesi-tance to emphasize race, but we can’t beafraid to say that in America prostate can-cer is different in African-Americanmen,” says Damon. “It’s a fact, and if we

are reluctant to talk about it, we are nevergoing to get this problem under control.”While he hopes for a greater impact,Damon says if his work gets just one manto talk to his doctor about prostate cancer,he feels he’s made a difference. Sharing his journey and his experience

at Johns Hopkins is one way he hopes toaccomplish that goal. “Johns Hopkins isthe greatest hospital in the world,” saysDamon. “I’m not a wealthy man as manywould expect or imagine, so it’s not mycelebrity that has earned me the besttreatment. In my experience, it’s repre-sentative of what Johns Hopkins deliversto each and every patient,” says Damon.Dr. Nelson points out that Damon

Harris is a perfect example of someonewho may have benefitted from screening.With so much attention focused on over-screening men, Dr. Nelson wants men tounderstand that screening is not bad;screening the wrong people is bad. Hesays, “What we need to do is targetprostate cancer screening to the rightmen, those who will benefit, and awayfrom those who will not.”Even though Damon missed the

opportunity for early detection and acure, he still considers himself a prostatecancer success story. At 62, he has livedwith advanced prostate cancer for 14years. He attributes his survival to a com-bination of “his doctors’ work and God’sgrace.” He says, “The Kimmel Cancer is asecond home to me. I feel certain that if Ihad not come to Johns Hopkins, I wouldnot be alive now.” Recently, the cancer has started to

grow again, and he is beginning radiationtreatment to knock down some painfultumors pressing on the nerves in his hipsand spine. He also is eager to begin treat-ment with a new FDA-approved drugcalled MDV-3100. He continues to beimpressed with the combination ofapproaches his doctors have used to keephis cancer under control. When drugtreatments have failed, he says, radiationtherapy has stabilized the cancer. Despite it all, Damon feels blessed. He

does not ask why or wonder what if. “Iwas given the gift of voice, and I am beingallowed to use that voice and to be heardthrough my music and my experience withcancer to help other people,” says Damon.“To have cancer is not to die,” he says. “Tohave cancer is to learn how to live.” •

“TO HAVE CANCERIS NOT TO DIE. TO HAVE CANCERIS TO LEARN HOWTO LIVE.”

R


Platz and her epidemiology colleagues fol-lowed nearly 50,000 men and compareddigoxin users to nondigoxin users andfound men who took the drug had a 25 percent lower risk of developing prostatecancer than those who did not. Now, theteam had laboratory evidence that digoxinhalted prostate cancer cell growth and apopulation study that found a significantlydecreased risk of prostate cancer amongmen who took the drug.It was unlikely a fluke. Getting the

same findings twice, once in the laborato-ry study and then in the population study,removed the likelihood that that theresults they were finding occurred bychance. Prostate cancer experts at JohnsHopkins and around the world deemedNelson and team’s laboratory/populationapproach quite smart. Combining the twotypes of research helped ensure that theinvestigators were not wasting time or limited resources pursuing a dead end.With good evidence that the heart drugtruly has anticancer properties, the

researchers are now working to figure outexactly how it works in prostate cancer. Digoxin has a number of side effects,

but Nelson says if they figure out how it works, they can develop or identifyanother drug that can safely treat or even prevent prostate cancer.

A TRAIN RIDE ANDTELOMERESRiding the train together on the way backfrom a prostate cancer meeting in 2004,researchers Alan Meeker, Angelo De Marzo,and Elizabeth Platz enthusiasticallyplanned the next phase of their break-through prostate cancer study. De Marzo is among the world’s best

prostate cancer pathologists, but what hecouldn’t figure out was why men withseemingly similar cancers under themicroscope often had very different outcomes in the clinic. What was different about their cancers,

De Marzo, Meeker, and Platz wondered.If they could figure it out, perhaps they

could develop treatments that would ben-efit all men. In this new age of molecularmedicine, was there something elsebeyond currently used pathology indica-tors—stage, Gleason grade, and PSA—hidden within the cancer cell that coulddetermine prognosis?It was 2004, four years before Johns

Hopkins researcher Carol Greider wouldwin a Nobel Prize for her research onchromosome ends known as telomeres.Similar to the plastic coverings that shieldthe ends of shoelaces from damage, onecan think of telomeres as the protective endcaps of chromosomes. Building uponGreider’s growing body of work, Meekerand De Marzo received a MarylandCigarette Restitution Fund grant to studytelomere length and its potential link tocancer. As normal cells age and divide,some of the telomere DNA is lost andtelomeres get shorter and shorter. Normalcells monitor the length of their telomeresand initiate cell death if they get too short.It was already well recognized that telom-eres were shorter in cancer cells than nor-mal cells. They wondered whether thismonitoring system breaks down in cancercells and whether assessing telomere lengthcould be a marker for prostate cancer aggres-siveness. In preliminary studies, the investi-gators examined precancerous prostatelesions and found much shorter telomeres. This finding was the focus of their con-

versation as they sat huddled on the trainoutlining the next step in their research.Their excitement about studying telomerelength to see if it could tell them somethingnew about prostate cancer aggressivenessand prognosis did not go unnoticed bytheir fellow passengers in the “quiet car.”Unaware of their cancer discovery andunappreciative of the chatter, Meeker, De Marzo, and Platz were soon asked tofind different seats on the train.With funding from the Department

of Defense, they began to study the ideasthey discussed on the train ride. Theyexamined telomere length in the chromo-somes of human prostate cancer cells andnearby cells from the stromal or connectivetissue surrounding the prostate that hadbeen preserved in a special specimen bankat Johns Hopkins. Cell by individual cell,a research fellow painstakingly circledevery relevant cell on digital images of tissue that were stained with a fluorescentdye to mark the telomeres. A computer-

PRO ANTIANGIOGENESISANTIANGIOGENESIS: IT’S A LONG word to describe cancer treatments that workby cutting off the blood supply that tumors need for nourishment and growth.

Clinician-scientist Hans Hammers is hoping to take what he’slearned from success using antiangiogenesis therapies for kidneycancer to better treat prostate cancer, where antiangiogenesishas not worked so well.Traditional chemotherapy does not work at all in kidney cancer.

The kidney, adept at flushing out toxins, gets rid of anticancerdrugs before they can go to work. Antiangiogenesis discoveries

totally changed the way kidney cancer is treated, Hammers says, and every antian-giogenesis agent they use targets a single pathway, known as VEGFVEGF helps tumors develop the blood vessels they need to grow and spread.

Targeting the pathway with treatment tears down vessels that have already formed,and blocks the development of new ones, and shrinks kidney cancers by half.Hammers believed he should be able to achieve the same response in prostate can-cer, but theses cancers were inexplicably resistant to the treatment. Animal studiesfunded by the Maryland Cigarette Restitution Fund allowed him to trace the resist-ance to very primitive cells that march away from the tumor and begin growing else-where in the body, in a process known as EMT. Hammers examined stable, treat-ment-responsive kidney and prostate cancers. When he altered tumor cells to initi-ate EMT, the cells became resistant to antiangiogenesis treatment. “What we see ina high Gleason grade, which represents the most aggressive prostate cancer, isessentially EMT occurring,” says Hammers. “Gleason rating is a depiction of EMT.”Hammers is working to decipher the specific cellular mechanisms involved in EMTand identify targets for treatment. He believes targeting EMT could make antiangiogenesis treatments effective against prostate cancer and potentially many other cancers as well. •

Hammers


ized method quantified telomere length,the number of short telomeres, long telom-eres, and mix of both. Meeker and DeMarzo developed the approach to completesuch a thorough and comprehensive exami-nation. No research team had ever lookedcell by cell, opting instead to study bulk tis-sue, primarily because it was a simpler andless labor-intensive process. Meeker recog-nized they could miss something doing itthat way. In fact, what they found couldonly be deciphered by a method like theone Meeker and De Marzo developed.The research team was surprised to learnthat it was not short telomeres in the can-cer cells that seemed to matter but ratherthe variability in the length of telomeresfrom cancer cell to cancer cell that influ-enced the outcome of men with prostatecancer. The unconventional approach was dead on. “If we had done it the wayeveryone else does it, we would havenever found this,” says Platz. “Some wereshorter. Some were longer, but it was thevariability from cell to cell that predictedlethal prostate cancer, and it could befound only by looking at each cell.”Variable telomere length in prostate

cancer cells and short telomere length inthe nearby stromal cells translated to amuch higher risk of dying from prostatecancer. Prostate cancer cells with lessvariability in telomere length and longertelomeres in the stromal cells marked aless aggressive form of prostate cancer.When they separated the samples basedon these characteristics and referencedback to the actual patients from whomthey were obtained, the investigatorsfound that only one man in the lower-vari-ability/longer telomeres group died fromhis cancer compared to 20 in the higher-variability/shorter telomeres group. “Themarker gives us information and detectshigh-risk disease independent of otherscreening and staging tests,” says Platz.With support from the Department of

Defense, the National Cancer InstituteProstate Cancer SPORE grant, and theJohns Hopkins Prostate Advisory Council,the research team is now working todevelop an automated approach to speedup the burdensome process of measuringtelomere length in individual cells. The team sees many potential applica-

tions for their discovery. “Maybe there aresubsets of men in whom we can usetelomere length to predict response to

treatment and determine precisely whattreatments will work for each patient,”Platz says. Examination of telomerelength could also be used to help identifymen whose cancer is likely to progressand would not be good candidates foractive surveillance. Conversely, it couldbe used to provide more evidence of low-risk disease and give reassurance tomen who are enrolled in active surveil-lance. “Treatment has side effects. Wedon’t want to give it to a man who doesnot need it or when we know it will nothelp,” says Platz. “Telomeres may be amarker we can use to individualize ourprostate cancer therapy to maximize benefit and minimize risks and adverseaffects for each patient.”

WONDERING ABOUTTHE WONDER FRUIT

THE IDEA for Michael Carducci’sclinical research of the pomegran-ate fruit actually came from the

Kimmel Cancer Center’s benefactor andnamesake Sidney Kimmel. A pomegranateproduct manufacturer was widely toutinga UCLA study that seemed to indicatethat the fruit had prostate cancer-fighting

properties. Kimmel wanted his cancercenter to figure out if it was true, andCenter Director William Nelson thoughtCarducci was just the person to sort it all out.Carducci, the AEGON Professor in

Prostate Cancer Research, decided not tolimit his work to pomegranates. There area range of natural products marketed forprostate health, and Carducci decided tofollow Kimmel’s lead and conduct studiesto look for real, scientific evidence thatthese natural ingredients had an effect onprostate cancer cells through clinicalstudies. He has recently completed studiesof pomegranate and is now beginning tolook at Vitamin D and soy protein as wellas muscadine grapes skins.The UCLA study found that pome-

granate juice slowed PSA doubling timein men who had prostate cancer, an indication that pomegranates could beslowing the progression of the disease.Carducci wanted to see if he could repli-cate these results and also determine if the amount a person consumes makes adifference. For his studies he used POMWonderful pomegranate extract capsulesbecause the product is 100 percent pome-

Carducci


Coffey's most recent researchfocuses on temperature and howit can be used to treat cancer

The Coffey WayDONALD COFFEY WAS RAISED IN THE HILLS OF BRISTOL, TENNESSEEIN THE 1930s. His father ran a service station. Neither of his parents finished highschool. He struggled in school himself—repeated grades, was asked to leave his firstcollege, and was rejected by 20 graduate schools. He never heard of Johns Hopkins orBaltimore, and never knew a doctor or anyone with cancer, but after praying and medi-tating, he had what he describes as an overwhelming desire to study cancer. The unlikely journey that brought him to Johns Hopkins was far from easy, but asJohns Hopkins leadership would soon recognize, one of academia’s worst students was an astute learner and even better teacher. Coffey became one of Johns Hopkinsforemost experts in prostate cancer and one of its most sought after professors.


In more than 50 years at JohnsHopkins, Coffey has racked up along list of accomplishments. Manyof the accolades are as unconven-

tional as the man. He served as actingchair of the Department of Pharmacologywithout ever taking a course in pharma-cology. With no medical degree, he helpedfound the Cancer Center in 1973 with itsfirst director Albert Owens and then ran itin 1987, and served as President of theAmerican Association of Cancer Researchfrom 1997 to 1998. The jovial, spectacled,southern-speaking Ben Franklin lookalike is a one-of-a-kind, and his story is asmuch about cancer research as it is aboutthe human spirit.The early research of Donald Coffey

was in many ways the bedrock on whichmodern genetic and epigenetic discoveriesat Johns Hopkins were built. In 1974, heturned the research world upside downchallenging the popular thought on howDNA was copied. At the time, little wasunderstood about DNA and genes. Mostresearchers were interested in under-standing what it was and what wasrecorded on it. Not surprising, Coffey hada different idea. He was interested in thestructure of the tape and how it wasorganized in the nucleus. He decided to

look at the core of the nucleus. It was arevolutionary idea. Most scientistsbelieved there was nothing inside the core.Popular thought was that there was no

single place in the cell where DNA wascopied. Instead, scientists hypothesizedthat DNA was like a tape and was repli-cated by a moving recording head, ofsorts, which ran along the stationary tape.Coffey disagreed. He believed the core ofthe nucleus was where DNA was copiedand that the tape-like DNA strands, ayard long, were coiled tightly inside thecell nucleus. For those born in the digital era, the

tape cassette and recorder analogy seemsoutdated, but one has to remember thisresearch was occurring in the 1970s.

With a $500,000 no-strings-attachedcancer research grant from Bristol Myers,Coffey brought together two young up-and-coming unknowns in the field of

cancer research, Drew Pardoll, an M.D.-Ph.D. student, and Bert Vogelstein, whoCoffey calls the only true genius he’sever met.Pardoll theorized that rather than

using one mobile recording head, theDNA tape was instead copied at thou-sands of fixed sites along what theydubbed the nuclear matrix. Coffeyexplains, “The nucleus has a skeleton toit. That’s the nuclear matrix. Attached tothat skeleton are recording heads, themachinery that replicates DNA. The DNAis organized in thousands of loops movingthrough these heads.” Vogelstein used aseries of calculations, which Coffeydescribes as too complex to translate, andshowed that Pardoll’s model could work.

Coffey recognized that a doubting scientif-ic community would not believe it unlessthey could see it, so they showed what allof it looked like through pictures and

Coffey

{THE COFFEY WAY}

“DON’T ASSUME ANYTHINGYOU CAN’T PROVE.”

{THE COFFEY WAY}

“THE EXPERIMENT THAT DOESN’T COMEOUT THE WAY YOU THINK IT SHOULD ISTHE ONLY EXPERIMENT THAT IS REALLYGOING TO TEACH YOU SOMETHING NEW.”


scale models. Coffey recalls, “Ken Pientaand I went to Sears and bought a jigsaw,and we built an award-winning scalemodel 175 feet long of a relaxed single loopof DNA magnified 25 million times.”Another scale model, this one just fourfeet long, was constructed to illustrate thesuper-coiled loops of DNA. What does all of this have to do with

cancer? For that, Coffey, the professorknown for using Slinkys, soap bubbles,soda cans, and a 175-foot long replica of aDNA loop to illustrate a point, turns tothe cassette recorder. He pops an audiocassette tape into a tape player andpleasing sounds of Johann Strauss’ BlueDanube waltz begin to play. Withoutwarning, it is interrupted by the RollingStones singing Get Off of My Cloud.Unexpectedly, the tape begins once againto play Blue Danube. “This is cancer,”says Coffey. “Cancer is like your body’sgenetic tape playing the wrong song at thewrong time,” explains Coffey. “The tapeis all mixed up and contains errors.Cancer is a problem of uncontrolled cellgrowth and differentiation, and I want toknow what tape is played and when.Pieces of the tape are in wrong place, andthere are errors in what is playing. Songsare played at the wrong time. Embryonicsongs are played when they should havebeen turned off.”

Of course, understanding what is onthe tape and how it is played has been oneof the greatest scientific contributions ofJohns Hopkins. Coffey’s studentsVogelstein and Pardoll became world-renowned scientists in their fields;Vogelstein as the most frequently citedresearcher in all of medicine for his workrevealing the genetic blueprint for cancerand Pardoll for his work in figuring outhow cancer cells evade the immune sys-tem. As for the tightly coiled loops ofDNA, Kimmel Cancer Center investigatorand leading epigenetics experts Stephen

Baylin and William Nelson showed thatthe coils and loops touch and interactwith many gene sites, creating a structurethat turns off tumor suppressor genes. Still, at the time of their discovery,

the notion of a matrix was met withskepticism. “It was amazing how theseyoung people here could prove this stuffagainst the greatest labs in the world,”says Coffey. Suddenly scientists atMIT and Princeton were doingsimilar experiments.Coffey was not blindly enamored of the

work that came from more prestigiousacademic institutions nor was he disre-garding of the observations of everydayfolks who learned their trade on the joband not in the classroom. He was as com-fortable conversing with the janitor as hewas with the CEO. This not only madehim a fine human being but also a stellarscientist. Coffey was interested in solvingproblems, and he was not someone moti-vated by notoriety or celebrity.He tells of a job he had when he was in

college working as a chemist for the NorthAmerican Rayon Company in Tennessee.They were having a problem with linesthat carried acid used in the production ofrayon. The acid would back up and spillall over the floor. Coffey was chargedwith finding out what was causing theproblem. He talked to everyone he could

think of, including Big John, a laborerwho worked in the basement of the build-ing. Big John tipped him off to a vibrationin a machine that started about 20 min-utes before the breakdowns occurred.This observation led Coffey to the cause ofthe problem. Coffey believed that to find answers,

one first had to ask the right questions. “Heliked to gather everyone’s ideas. He madepeople feel like no idea would ever belooked at as being stupid,” recalls Pardoll.Coffey and Big John became instant

legends at the North American Rayon

Company, and his boss there, a JohnsHopkins alumnus, inspired him to go toBaltimore. He boss told Coffey, “You’llhave to work your way in, but they’ll takecare of you. When you hit the ball theydon’t care who you are.” “I was a C student from East Tennessee

State University, and now I was planningto go to Johns Hopkins,” says Coffey.(Before Tennessee State, he attendedKings College. The college president sug-gested he leave after hiring a plane to droppolitical leaflets, some of which got wetand dangerously fell to the earth like a cin-der block. Years later, Kings College gavehim an honorary doctorate.) Coffey discussed it with his wife Eula,

and they agreed they should move toBaltimore. By day, Coffey worked atWestinghouse designing radar antennas.In the evening, he took classes and gothis foot in the laboratory door by wash-ing glassware for graduate students.After receiving a glowing reference fromhis former employer at North AmericanRayon, the School of Medicine hired himto work evenings in the urology lab. Ayear later, in 1959, with no graduatedegree, he was named the acting directorof the Brady Urological ResearchLaboratory. “The starting salary was$5,000. I was making $18,000 atWestinghouse, but I knew I wanted to docancer research.” After a year of runningthe lab, he was accepted to the School ofMedicine’s graduate program inPhysiological Chemistry. Coffey earned his Ph.D. at 33. By then,

he had already been a chemist, an engi-neer, a laboratory director, and prostatecancer researcher. Everybody wantedhim, and Professor Paul Talalay hiredhim to the Pharmacology Department fac-ulty. Soon thereafter, Professor WilliamScott invited him to join the faculty of theUrology Department. Coffey’s meteoricrise from his self-described role as “chiefbottle washer” to become the CatherineIola and J. Smith Michael DistinguishedProfessor of Urology; professor ofOncology, Pharmacology and MolecularSciences, and Pathology; and a member ofthe professional staff of the AppliedPhysics Laboratory seemed right out of aHollywood movie.In fact, despite his academic struggles,

Coffey was a perfect fit for Johns Hopkins.He believed that much could be learned if

{THE COFFEY WAY}

“IF YOU FIND SOMETHING TO BETRUE, WHAT DOES IT IMPLY? OFTENWE DON’T NEED MORE EXPERIMENTS.WE NEED MORE CRITICAL THINKINGABOUT THE RESULTS.”


people from different disciplines wouldjust get together and talk about a problem.“People like to visualize a disease as onething wrong. Like, there’s a wire loose incar, but it’s never just one wire in a car.By the same reasoning, it takes multiplesteps to form a cancer cell. There’s anaging phenomenon associated with it, agenetic phenomenon, and a whole bunchof environmental and epigenetic factors.Man, I hate to tell you how often peoplefrom all those different fields don’t gettogether in science,” says Coffey.

For Coffey, neither the classroom northe laboratory ever closed. In the hall-ways of the Brady, in his office over hightea, or in a conference room, Coffey couldbe found fostering collaborations andinspiring innovative ideas about cancer.It was not unusual for these discussionsto last long after business hours. The nextmorning, equations and notes jottedacross blackboards were evidence to thelively discussions that had occurred thenight before.Coffey, who suffers from dyslexia, pro-

foundly understands that everyone learnsdifferently. The disorder that caused himto struggle as a student helped make himone of the world’s greatest teachers. Among his many revered lessons is

what he calls the “Real Final Exam.” In it,he extols several time-tested principles.In fact, the last one is a favorite of

Coffey’s who sometimes seems to espousecredit for everyone but himself. Back atNorth American Rayon Company, thoughhe put all of the pieces together to solve theacid line problem, he quickly redirectedcredit to Big John and secured him a size-able raise. He talks willingly and withpride about the accomplished researchersand clinicians who have come through hislaboratory. Rightfully so, as the list readslike a who’s who in cancer. In addition toVogelstein and Pardoll, it includes KimmelCancer Center Director William Nelson,

Urology Director Alan Partin, RadiationOncology and Molecular Radiation ScienceDirector Ted DeWeese, and ProstateCancer Foundation President and CEOJonathan Simons, to name just a few.Coffey continues to patrol the hallways

of Johns Hopkins in search of new talent.He has a simple formula for finding thebest and brightest. He asks people. Itcould be other professors or students, oreven patients. He asks them, who is thesmartest? Who is the best? Then, herecruits these rising stars to the fight

against cancer. As the list of his recruitsattests, the formula is one that works. Coffey turned 80 on October 10, 2012,

but age has done little to quell his questfor knowledge. His most recent researchexamines the shared traits between bacte-ria and cancer cells. Coffey and his col-laborators believe that cancer cells, likebacteria, rely on communication and“social networking” to survive and thrivewithin the body. Cancer cells and bacte-ria use chemicals and gene pathways tooverride controls that tell cells how tobehave, he says. He hopes that betterunderstanding the social behavior of cancer cells—intricate cell-to-cell commu-nication they use to grow, spread, andevade treatments—will inspire new therapeutic approaches.

Coffey was also part of a team thatused a testicular cancer model to provethat cancer cells that are exposed to heatare easier to kill with anticancer drugsand radiation therapy. They showed thateven advanced cancers that have spread

to other parts of the body could be reinedin with heat. To develop it clinically,Coffey, Radiation Oncology Director TedDeWeese, and scientists Robert Ivkof,Shawn Lupold, and Prakash Kulkarni areusing small antibodies that attach to ironparticles which, in turn, naturally attachto cancer cells throughout the body.When exposed to alternating magneticfields, the iron particles vibrate enough toheat up the cancer cells so they becomemore vulnerable to therapies. Coffey says these discoveries have led

to a new fascination with temperature. Interms of personalized medicine, Coffeypoints out, temperature, as fever, is onethe of primary measurements used todetermine whether someone is sick—andhe ticks off a multitude of questions: “I amtrying to understand temperature and thescientific and evolutionary reason for theprecise body temperature of 98.6°. Why isit not 87° or 103°, and why does a chickenegg hatch at approximately 100°? Why is ahurricane caused by only a few degreeschange in ocean surface temperature? Whydoes a flame form in a precise structure ona candle? And why does a woman's tem-perature go up a few degrees when sheovulates? Why is the sex of an alligator andturtle decided at precisely 100°? And whydoes a man's sperm not survive body tem-perature? Why do snowflakes form suchinteresting patterns? How does life formagainst the second law of thermodynamicsof increased entropy and heat? How canthis heat and temperature be used to cureinfections and to treat cancer and to germi-nate acorns and to form the precise treeline on the mountain?”While the answers to these questions

may, for the time being, remain a mystery,one thing is certain. In the inquisitive

mind of Donald Coffey, nothing changesbut the birthday. His enthusiastic andcontinuing quest for knowledge promisesto bring Johns Hopkins and the worldmore unexpected discoveries, unusualprops, and riveting lectures. •

{THE COFFEY WAY}

“WHEN DISCOVERIES ARE MADE, GIVEEVERYONE CREDIT. YOU WERE PROBA-BLY NOT THE FIRST ONE TO STUDY THEPROBLEM, NOR WILL YOU BE THE LAST.”

{THE COFFEY WAY}

“GENERATE MORE THAN ONE CONCEPTTO EXPLAIN YOUR DATA, THEN GIVE ALLTHE POSSIBILITIES YOUR EQUAL ATTEN-TION AND EFFORT. YOUR PET IDEA WILLUSUALLY TURN OUT TO BE JUST THAT.”


granate. Regarding the pomegranateindustry, he cautions buyer beware, asthe demand for the fruit is 15 times greaterthan production. Many products on themarket contain a very small amount ofpomegranate juice mixed with blueberry,grape, acai or other juices. Carducci sayspomegranate is of interest to cancerresearchers because it is the highest inantioxidants, chemicals known to havecancer-fighting properties. Carducci and his team, which includes

Emmanuel Antonarakis and ChanningPaller, are still sorting through their find-ings. They confirmed the findings of theUCLA study, also finding that PSA dou-bling time slowed, an indication, but notproof, that it has an impact on the pro-gression of the disease. Moreover, theyresolved the “how much is enough” issue,and showed that low doses of the extracthad the same effects as higher doses. “Wehave to verify that the affect we’re seeingis caused by the pomegranate and not justa natural process we’re picking upbecause we’re watching more closely,”says Carducci. “We think that slowingPSA is good thing, but we have to provethat it actually makes a difference inpatient outcomes,” he says.Another similar study in partnership

with Howard University is exploring thebenefits of muscadine grapes. The skin ofthese large, dark-purple grapes contains

two antioxidants, resveratrol, which iscommon to grapes, and ellagic acid, thesame antioxidant in pomegranates. Carducci hopes that their studies will

lead them to alternative therapies for menwhose PSA begins to rise after surgery,an event called biochemical recurrence.One option for these men is hormonaltherapy, but these therapies have annoy-ing side affects such as weight gain andhot flashes and, even more of a concern,they may accelerate heart disease. “Ifthere is a more natural approach thatwould allow these patients to avoidadverse affects, it would be very exciting,”says Carducci.

TRACING THE MUDDLEDGENEALOGY OF PROSTATECANCER

IT TOOK 20 years of work, but aresearch team led by prostate cancerlaboratory scientist William Isaacs has

uncovered the genetic driver for a heredi-tary form of prostate cancer that tends tostrike younger men. It is the first majorgene finding associated with inheritedprostate cancer.“It’s long been clear that prostate cancer

can run in families, but pinpointing theunderlying genetic basis has been challeng-ing and earlier studies have providedinconsistent results,” says Isaacs, theWilliam Thomas Gerrard, Mario Anthony

JOHNS HOPKINS PROSTATECANCER MILESTONES

• Performed the first prostatectomy in 1904 and later pioneered theanatomical nerve-sparing approach

• Developed some of the first therapeuticapproaches and clinical models forprostate cancer, including the earliestform of brachytherapy, and were thefirst to culture human prostate cancercells to study therapeutic targets

• Developed the first animal models tocharacterize the properties and types ofprostate cancer; the models were sent

• Discovered the first human gene mutation in prostate cancer

• Deciphered the mechanisms forprostate cancer metastasis

• Provided the first description of thebasic cellular and molecular propertiesof prostate cancer

• Were the first to describe the impor-tance of stem cells in prostate cancer

• Deciphered how prostate cancergrowth is regulated

• Defined hereditary prostate cancer

• Performed the first DNA methylationstudies in prostate cancer

• Developed an animal model of prostateinflammation and defined PIA (prolifera-tive inflammatory atrophy), a new modelfor what causes prostate cancer

• Pioneered quantitative pathology torefine staging and prognostic markers

• Developed the Partin Tables, PoundTables and Han Tables to predict localized cancers, relapse time, metastasis and survival

• Used PSA velocity to define lethal types of prostate cancer

• Developed and clinically tested the firstprostate-specific adenovirus to treatrecurrent and metastatic prostate cancer

• Performed the first protein analysis ofnormal prostate and prostate cancer

• Developed new biomarker tests forprostate cancer

• Led the work in robotics for prostatecancer treatment

• Pioneered tumor immunology studiesand developed GVAX, the first therapeutic vaccine for prostate cancer

• Identified new drug targets, PSA-activated prodrugs, and other agents

Isaacs


Duhon and Jennifer and John ChalstyProfessor of Urology.Isaacs’s work was inspired two decades

ago by the pioneering work of BertVogelstein and team that uncovered geneticalterations linked to hereditary forms ofcolon cancer. These findings led to cancerbeing defined as a genetic disease and ulti-mately revealed the complex landscape ofcolon and other cancers among the generalpopulation. Unlike colon cancer, whichprovided inherited syndromes and earlyonset of disease as clues, in prostate cancer“there were no syndromes families where25-year-olds were getting the disease, andwe could study them,” says Isaacs. It was frustrating for Isaacs because ear-

lier studies seemed to indicate that prostatecancer had a strong hereditary susceptibili-ty, higher than colon and breast. Wherewas it? Why couldn’t they find it?It turns out that techniques that worked

so well in defining the genetic culprits forcolon and breast cancer did not work sowell with prostate cancer. “It’s a diseasethat most men get,” says Isaacs. He pointsto volumes of books on his shelf that con-tain pedigrees of families where three orfour families had prostate cancer. “It is themost common cancer in men. We are goingto find families with multiple members whohave the disease, even without a geneticcomponent, just because it is so common.”Tweezing out which ones were geneticallylinked and which ones were not turned outto be a monumental task.With other cancers, early age at diagno-

sis is a red flag for a hereditary link. Inprostate cancer, the best determinant ofearly age of diagnosis relates directly tohow early a person is screened. “If youhave a 20 year old with a lump in herbreast, you know it’s early onset,” saysIsaacs. “With prostate cancer, you couldhave a guy diagnosed at 75 who may havehad the tumor since he was 45 or younger.”It is well known that prostate cancer is aslow-growing cancer and autopsy studiesdone at Johns Hopkins have revealed earlycancers in men in their twenties and thir-ties. “We wouldn’t know if a man hadprostate cancer at 25 because no onescreens for it at that age, and he probablywouldn’t have any symptoms that wouldcause him to see a doctor,” says Isaacs.Enter PSA. Now men were being diag-

nosed in their 40s and 50s, and they wantedto come to Johns Hopkins to have Patrick

Walsh take their prostates out because hewas the only guy in the world that could doit without leaving them impotent andincontinent. Over a five-year period,prostatectomy went from a surgery rarelydone to the most common surgery per-formed at Johns Hopkins. Walsh was ask-ing his patients about family history, andsome of them were telling him that theirgrandfather, father, brothers all hadprostate cancer. Influenced by the lateBarton Childs, a legendary Johns Hopkinspediatrician and geneticist that shaped theunderstanding of inherited disease, Walshbegan cataloging prostate tumors to charac-terize a hereditary form of the cancer. Bob Carter, a young medical student

working with Isaacs and Bloomberg Schoolof Public Health investigator Terri Beatty,asked Walsh if he could look at his first 600patients, and using their wives as controlsdetermined that if a man has prostate cancer or one of his brother’s has prostatecancer, the other brothers were at risk.This 1990 finding reignited the search foran inherited form of prostate cancer and the gene or genes behind it. Isaacs wasintrigued. The group put an ad in Parade Magazine

seeking volunteers with a family history ofprostate cancer. Within two weeks, theyhad 2,500 men who responded and wereeager to help decipher the disease. Publicannouncements by General NormanSchwarzkopf, Senator Robert Dole, and fin-ancier Michael Milken about their owndiagnoses with prostate cancer all con-spired to bring attention and interest to thedisease. “Research ticked up, but when thesmoke cleared 15 years later, we still didn’thave anything particularly useful,” saysIsaacs. “A few genes turned up, but theireffects turned out to be small.”Then, in the mid 2000s a new idea was

being explored. Adopting the premise thathumans are really all one big happy familyextending from a small number of originalfounders, there should be a limited numberof founder chromosomes in the population.Bert Vogelstein’s research revealed foundergene mutations associated with cancer inthe Ashkenazi population. “The samething occurs with everyone on the planet.It’s just harder to find,” says Isaacs. TheHapMap Project, an international endeavorto describe the common patterns of humangenetic variations, was beginning and theirwork had the potential to shed new light on

the problem. It did. “In six years, we wentfrom having no genetic risk factors forprostate cancer to as many as 70,” saysIsaacs. “For the first time we could deter-mine increased genetic risk, but the effectwas small, increasing risk by 10 to 20 per-cent, so there really was no clinical implica-tion,” says Isaacs.At Johns Hopkins, with the mission of

using science to improve patient care, thefindings were disappointing for an addi-tional reason. “It didn’t tell us what type of prostate cancer men were at risk for or if it should be treated,” says Isaacs. “Again,we were running into the same wall.”“Here’s the dilemma. We know statisti-

cally that most prostate cancers are notgoing to progress to a point where qualityof life is affected. Most men will be fine, so we say we are overdiagnosing andovertreating men,” says Isaacs. “But,prostate cancer is the second leading causeof cancer death in men. We’re not over-diagnosing and overtreating these men. To the contrary, I’d say these men areunderdiagnosed and undertreated.”So, in the United States, we have erred

toward caution, Isaacs says, because wehave not yet been able to unearth the genet-ic factors that will definitively separate theslow growing cancers from the aggressiveones. In some countries in Europe, theopposite approach is taken and prostatecancer is rarely treated because of the finan-cial burden it would place on its socializedmedical system.“Prostate cancer is tailor-made for

personalized medicine, but we need to figure out what predicts aggressive disease,” says Isaacs. In the meantime, Isaacs heads an inter-

national consortium for prostate cancergenetics funded by the National CancerInstitute. Investigators at the University of Michigan, one of the participant groups,were getting a reproducible hits in theirresearched that pointed them to a region onchromosome 17. An examination of thisregion in the prostate cancer families col-lected at Hopkins revealed the same butweaker signal. Some of the most interestinggenes in this region were members of theHOX gene family. The earliest informationon these genes evolved from fruit fly studies.

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Isaacs recalls a prominent jour-nal that had displayed a photoof a fruit fly on its cover. Thefly had legs coming out of itshead where its antennae shouldbe due to a HOX mutation.“The legs were perfectly nor-mal, except they were growingin the wrong place,” saysIsaacs. Kimmel Cancer Centerbreast cancer researcher andBarbara Rubenstein Professorof Oncology SaraswatiSukumar was an expert onHOX proteins and had associat-ed them with breast cancerdevelopment and resistance tochemotherapy. “We knew fromprevious work that specificHOX genes were very impor-tant in normal prostate devel-opment in mice. What if it wassomehow linked to the growthof prostate cells in humans,” hewondered. Isaacs was interested in a partic-ular gene in the HOX family, HOXB13. Inmice, this gene is turned on just at the timethe prostate is developing. Working with the University of Michigan

group, Isaacs focused his research on fami-lies with alterations on chromosome 17.One of these families had nine memberswith prostate cancer, and he had DNA fromseven of them. The University of Michiganteam had three families where all of themembers with prostate cancer had thesame HOXB13 mutation. Isaacs had tomake sure it wasn’t simply a result of themutation being common in the population,so he started genotyping everyone he couldfind, regardless of family history, andincluding men without prostate cancer.He looked at 5,000 samples and found themutation was extremely rare in the generalpopulation, but in the men who had it, ittranslated to a ten times greater risk ofdeveloping prostate cancer. Finally, theyalso had the significant link to early onsetthat Barton Childs had pointed to so manyyears earlier. The mutation was mostprevalent among men diagnosed early,under age 55, and many of them had afather or brother who had prostate cancer.Now he had met both of Child’s require-

ments: early onset of disease and familyhistory; and he had zeroed in on the cause.The mutation was rare in men diagnosedover age 65 with no family history.It was a textbook case. On one hand,

Isaacs was incredibly excited, on the other,he was not finding the indisputable link toaggressive disease he had hoped for, or, forthat matter, one that conclusively pointedto an indolent form of the disease. “Rightnow, it doesn’t help us with that criticalquestion of who to treat and who not totreat, but we feel like we’re on the righttrack,” says Isaacs. The mutation was most prevalent in

families of European descent. Isaacs founda different HOXB13 mutation in men ofAfrican descent, and another team of investigators found yet another mutation in Han Chinese men. “It appears there aredifferent founder mutations for differentethnicities,” says Isaacs. It could be usefulfor families where a member had an aggressive prostate cancer associated withthe mutation. “We could potentially test the other men in the family to see if theyhave mutation so that those who carried itit could be monitored more closely and atan earlier time,” says Isaacs.He continues to delve deeper into the

causes of prostate cancer in African-American men where incidence and deathrates are double those of white men.“Treatment is effective, and so we have to

figure out how to get to these men when itwill work,” says Isaacs. There are somemen, he suspects who could benefit frommuch earlier PSA screening, perhaps start-ing as young as 25 or 30. Prostate cancerclinician-scientist Michael Carducci agrees.“Research finds that it is the 50-year-oldguy who is more likely now to present withmetastatic disease than the guy who is 65 or75,” says Carducci. “Maybe there should bean early check to find these guys. We’retrying to figure that out, so together, ourresearch group is evaluating limited butearly screening for men at highest risk.”In the end, Isaacs says, “It’s a mixed bag.

I’m very excited about this discovery, but I also realize that this is a tough cancer tofigure out, and there is still much work tobe done. The good news, Isaacs says, is thatat Johns Hopkins, the experts have knownthis, so we’re ahead of the curve. The prognostic question—which cancers willprogress and kill and which ones will not—is the single most important question inprostate cancer.”

UNPRECEDENTED STRIDESThe last few years have seen unprece-dented strides in drug discovery forprostate cancer. Six new drugs have beenapproved and prostate cancer clinicianMario Eisenberger, the R. Dale HughesProfessor of Oncology, is working with fellow clinical investigators Michael

Eisenberger and Antonarakis

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Thapsia garganica is a 3-foot tall weed that grows wild and abun-dantly in the Mediterranean. It is abundant because of its not so

favorable reputation. Ancient Greek writ-ings refer to it as the “plant of death” andArabs named the weed the “death carrot”when they witnessed that camels who ate itquickly died. In the late 1970s, a Danishchemist isolated its toxin, calling it thapsi-gargin. Kimmel Cancer Center researcherJohn Isaacs began collaborating with thechemist in hopes of harnessing its killingpower to treat prostate cancer.Thapsigargin, Isaacs found, indeed killedprostate cancer cells, but unfortunately it

also killed heart cells and brain cells. “We gave it to mice, and theywere dead within minutes,” he recalls.

Undeterred, Isaacs, one of the world’s leading experts inapoptosis (cell death through the natural cell life cycle) began putting his extensive understanding of how cells die to formulate aversion of the toxin that would be lethal only to cancer cells. Herecruited the help of fellow prostate cancer researcher and clinicianSamuel Denmeade, and for more than a decade the two worked tochemically modify the toxic weed to specifically and safely targetprostate cancer cells.

Thapsigargin kills by making cells think they need calciumwhen they do not, Denmeade explains. As a result, cells are floodedwith unending amounts of calcium and die. The trick was to re-engineer the lethal toxin to deliver its killing power only toprostate cancer cells. For this, Denmeade and Isaacs created acompound that remains inactive until it comes in contact with cellsthat secrete a protein known as the prostate-specific membraneantigen (PSMA). This modification meant that the toxin would now selectively target the prostate and, unlike its predecessor,would leave heart cells, brain cells, and other normal cells alone. In laboratory studies that used human prostate tumors transplanted

into mice, their engineered drug looked promising. A three-daycourse of the drug shrunk tumors in half and outperformed otherstandard cancer drugs.

With critical funding from David H. Koch, investigators Isaacsand Denmeade worked with Michael Carducci, Angelo De Marzo,and other Kimmel Cancer Center prostate cancer experts and colleagues to take their discovery to patients. Denmeade likenedtheir chemically modified form of thapsigargin to a medicinalgrenade. When the drug comes in contact with PSMA-secretingcells, it pulls the pin killing all prostate cancer cells in its vicinity.

Delivered by injection, the drug, now called G202, works byblocking the function of an essential protein that keeps calcium levels in cells at the correct level. In essence, it causes tumor cellsto overdose on calcium and die. It also shuts down the blood vessels that feed prostate tumors.

Contrary to its namesake, the research team says PSMA is notonly found in the prostate but also in blood vessels in brain, kidney,bladder, breast, colon, and lung cancers, so it has the potential towork against many different types of cancer. Laboratory findings inbreast, kidney, and bladder cancers reported by the team in ScienceTranslational Medicine support this theory.

To date, the Johns Hopkins team, and collaborators from theUniversity of Wisconsin and the University of Texas-San Antonio, hastreated 29 patients with advanced cancer in a clinical trial assessingthe safety of the drug. New trials will evaluate the safety and theeffectiveness of G202 in patients with prostate and liver cancers.

“What we like best about this drug,” says Isaacs, “is that itcauses the cancer cell itself to bring about its own demise.” •Editor’s Note: This research was funded by the Department of DefenseProstate Cancer Research Program, the Prostate Cancer Foundation,David Koch, the Danish Cancer Society, the Danish Research Council,the Aarhus University Research Foundation, and the NationalInstitute of Health’s National Cancer Institute SPORE(CA058236 and CA006973).

DEATH CARROTA MOLECULAR GRENADE FOR CANCER


Carducci, Sam Denmeade, EmmanuelAntonarakis, and others to determinehow to best integrate them into clinicalpractice. “We have to figure out whoshould get which drug or combination ofdrugs,” says Carducci. Carducci says the drug discovery

pipeline at the Kimmel Cancer Center hasplayed a key role in advancing the treatmentof prostate cancer. Drugs like Tasquinimod,an interesting new agent that appears towork both through the immune system andby cutting off the blood and nourishmentthat tumors need to grow and spread, arefinding much success.Eisenberger believes a $1.5 million gift

from Jones Day, a Washington, D.C.-basedlaw firm, will strengthen these advancesby supporting work to identify molecularsignatures that allow for personalizedtherapies and improve quality of life formen with prostate cancer. It will fundseveral projects, including a tissue bank,laboratory and clinical collaborationsaimed at rapidly identifying new targetedimmune and drug therapies, and the iden-

tification of new biomarkers for monitor-ing disease progression and treatmenteffectiveness. Eisenberger and team areexploring various novel approaches,including natural compounds that couldprevent or keep prostate cancer in check,targeted hormone therapies, and immuneapproaches that sensitize prostate cancercells to drug treatment.The gift will also help support the work

of laboratory scientists, includingSrinivasan Yegnasubramanian who isworking to identify biologic markers ofresponse to treatment. “We want tounderstand why two men with metastaticprostate cancer and similar clinical fea-tures and tumor pathology can have drasti-cally different responses to the same thera-py,” says Eisenberger. They are studyingtumor samples from 60 patients whosecancer spread to the bones and other sitesand were then treated with androgen deprivation therapy, a type of therapy thatsuppresses androgen, a hormone that isknown to fuel the growth and spread ofprostate cancer. “If we can uncover molec-

ular genetic clues that predict which cancersare predestined to be sensitive to treatment,we may be able to personalize treatments,”he says. “Conversely, we can use geneticbiomarkers to identify men who will notrespond to hormone therapy and designbetter treatments for this group.” “The generous contribution from Jones

Day allows us to take on these projects,”says Eisenberger. “As a result, we expectto improve and prolong the lives of menwith prostate cancer.”

THERANOSTICS AND MOREIn a new approach dubbed “theranostics”because it combines the diagnostic prop-erties of molecular imaging with cancertherapy, a multidisciplinary team ofexperts, including Radiation OncologyDirector Ted DeWeese, and cancer imag-ing experts Martin Pomper and ZaverBhujwalla, developed an idea that takesadvantage of important molecular compo-nents of cancer and allows researchersand clinicians to see inside the cancer celland view them as they are being treated.

The team is developing ultra-tiny structures called nanopar-ticles filled with an anticancerdrug that also sensitizes cancer cells to radiation and a radiopharmaceutical or cell-imaging agent. Thenanoparticle is targeted toPMSA, a biomarker forprostate cancer, so that itzeroes in on and delivers itsanticancer payload specificallyto prostate tumors. The particleis labeled with a radioactiveisotope, which can be imagedor used to treat cancer. It isgiven intravenously so that it can attack cells growinganywhere in the body.In other work, DeWeese

and prostate cancer researcherShawn Lupold became the firstto show that targeted smallinhibitory RNA (siRNA) couldbe used for prostate cancertherapy. This breakthroughresearch focuses on siRNA,small molecules that have theability to interfere with theexpression of genes. DeWeeseand Lupold used aptamers, aguidance system of sorts, to get

DeWeese


the RNA molecule to its target inside ofcancer cells where it shuts down cancercells’ ability to repair the injury that radia-tion inflicts and, as a result, they die. Theaptamers, which allow the repair-blockinginhibitory molecules to be targeted specifi-cally to cancer cells, are unique to JohnsHopkins and considered the gold stan-dard. Moreover, it is a platform technolo-gy that can be used not only for prostatecancer but any cancer type, simply bychanging the aptamer. Yet another nanotech approach

DeWeese is exploring for prostate cancertreatment uses alpha particles, a type ofradium isotope, that are naturally target-ed to the bone where prostate cancer mostoften spreads. It captures the killingpower of decaying radium, but in thisform it has a short life of about ten daysand only causes damage in the limitedpath it travels in the body. Radium has achemical relationship to calcium, and soacts in the human body like calcium, naturally traveling to the bone.Investigators are studying a combinednanoparticle/alpha particle/radiationtreatment. The nanoparticle, loaded withits radiation-sensitizing anticancer drug,is given simultaneously with the bone-metastasis-targeting alpha particle toexquisitely and precisely attack prostatecancer and its spread.

FIRST-OF-ITS-KINDTREATMENTA first-of-its-kind prostate cancer com-bined therapy will make surgery anoption for more men. Clinical studies, ledby Charles Drake, a cancer immunologyexpert and co-director of the ProstateCancer Multidisciplinary Clinic, willinclude a prostate cancer vaccine. GVAX,the immune system-boosting vaccinedeveloped more than a decade ago byKimmel Cancer Center investigators willbe given after surgery in combinationwith the anticancer drug cyclophos-phamide and a new prostate hormonetherapy drug called MDV 3100. The treat-ment is for men who are diagnosed withhigh-grade prostate cancers that are likelyto recur. In the past, these men were notcandidates for surgery because of the like-lihood that microscopic tumor cells, invis-ible to surgeons, had already broken awayfrom the tumor and destined the cancer toreturn. Drake, who is collaborating with

medical oncologist EmmanuelAntonarakis and urologists Alan Partinand Edward Schaeffer, is excited to have apotentially curative treatment to offerthese men. They hope to find out whatimmune cells are already present at thetime of prostatectomy and figure whatarmy of immune cells they need to causean attack against prostate cancer cells.They believe the vaccine/drug treatmentcould work to mop up the microscopiccancer cells missed at surgery.

REHAB AFTER PROSTATECANCER TREATMENTThe two big quality-of-life issues that menexperience following prostate cancer sur-gery are urinary incontinence and erectiledysfunction. Urologic oncologist andprostate cancer surgeon TrinityBivalacqua and nurse practitioner KristenBurns are helping men through a newrehabilitation/survivorship clinic.Bivalacqua is skilled at both open androbotic prostatectomy, giving him boththe unique perspective and the experienceto help men recover from prostate cancersurgery. “If we’re going to work to cureeveryone, we want be sure we also try toeliminate the adverse quality of lifeissues,” says Brady Urological InstituteDirector Alan Partin. Any prostate cancerpatient who receives surgery or radiationtherapy is a candidate for rehabilitation.Some men who experience problems mayonly need counseling while others couldrequire a more invasive intervention toalleviate symptoms, but the team says theywant patients to know that this service ispart of the care we offer them. Initially,they will focus on Johns Hopkins prostatecancer patients only, but eventually theyhope to expand the program to helppatients across the country. •

TITANS OF PROSTATE CANCERFollowing the Johns Hopkins model, leaders in the Prostate Cancer Program never disconnecteddiscovery from the patient. Keeping the twoaligned, its investigators and clinicians have mademore advances than any other place in the world.

FOR MORE ON PROSTATE CANCER


PROSTATE CANCERLEGENDUrologist Patrick Walsh is perhapsthe most famous and revered figurein the world of prostate cancer. For 30 years he served as director ofthe internationally renowned BradyUrological Institute at Johns Hopkins.He transformed prostate surgery bydeveloping an anatomical approach toremove the cancerous prostate with-out causing life-changing side effects,taught the procedure to hundreds ofurologists-in-training; and gatheredinformation from patients that propelledprostate cancer research forward. In June 2011, he performed the procedure he pioneered for the lasttime. It was his 4,569th prostatectomy.He remains a familiar figure at “TheBrady,” and through the Patrick C.Walsh Prostate Cancer Research Fundcontinues to advance the understand-ing and care of prostate cancer. •

Walsh

Erick Lutz, Ph.D., has joined theGastrointestinal (GI) Cancer Program asan assistant professor of oncology. Lutz isthe fourth Viragh Research Scholar fromthe Skip Viragh Clinical Research Centerin Pancreas Cancer. He will develop ahuman immunology laboratory programfor GI cancers focused on deciphering theimmune response within the tumormicroenvironment. Dr. Lutz completed hisfellowship under the mentorship ofElizabeth Jaffee, M.D., uncovering thebasic immunologic principles that defineimmunotherapy-induced immune responsesand developing new technologies to studyimmune responses within developinghuman tumors.

Channing J. Paller, M.D., assistant pro-fessor of oncology, will extend genitouri-nary cancer services to the Washington,D.C. campus of the Kimmel Cancer Center.Paller is a clinician-scientist focused ondeveloping and evaluating new therapies forurologic malignancies, including prostatecancer. She is particularly interested in therole of natural products for prevention ortreatment of prostate cancer. As a fellow,she worked with Michael Carducci, M.D.,to study the benefits of pomegranateextract and muscadine grape skin extractfor men with prostate cancer and earnedYoung Investigator Awards from theAmerican Society of Clinical Oncology andEastern Cooperative Oncology Group.

Deborah Schwartz, R.N., M.P.H.,C.R.N.P., has joined the Kimmel CancerCenter Hematology Service as a nursepractitioner. She will support the develop-ment of critical pathways and educationalprograms to standardize hematology care.She is currently completing the credential-ing process to perform lumbar punctures,bone marrow aspirates, and conscioussedation. Her previous experience includescaring for critically ill pediatric and adultburn patients in a level one-trauma center.

IN THE NEWSTHE LATEST CANCER NEWS from the JOHNS HOPKINS KIMMEL CANCER CENTER


NEW APPOINTMENTS AND ARRIVALS

Amy DeZern, M.D., assistant professor ofoncology is a new member of theHematologic Malignancies and BoneMarrow Transplant Program. She is a distinguished clinician and clinical investi-gator who trained with Kimmel CancerCenter hematology and oncology expertsRobert Brodsky, M.D., and Mark Levis,M.D. In addition, she earned her master’sin health science from the BloombergSchool of Public Health. Her work willinclude development of a translational clinical investigation program focused on malignant and non-malignant bonemarrow failure states.

Ivana Gojo, M.D., associate professor ofoncology, has joined the HematologicMalignancies and Bone Marrow TransplantProgram. She will work with Dr. JudyKarp to direct leukemia drug development.Her clinical research in leukemia, includ-ing the development of several leukemiatrials, is nationally recognized.

Edward Harhaj, Ph.D., has been appoint-ed an associate professor of oncology inthe Viral Oncology Program. He is a basicscientist who has conducted seminal workin the area of inflammation and viral inter-ference with natural immune responses.He is a recognized leader in the biology ofthe Human T-Cell Lymphotropic Virus-1(HTLV-1) and NF-kBm, which plays a keyrole in regulating immune response.HTLV-1 is linked to HTLV-1 AssociatedMyelopathy/Tropical Spastic Paraparesis,a neuroinflammatory disorder similar tomultiple sclerosis and an aggressive T cellleukemia known as adult T cellleukemia/lymphoma (ATLL).


Richard Zellars, M.D., associate professor of radia-tion oncology, and Dina George Lansey, M.S.N,R.N, O.C.N., Research Associate and ClinicalRecruitment Specialist, are heading the KimmelCancer Center’s initiative to increase minority accrualto clinical trials. Zellars has been appointed AssistantDirector for Clinical Trial Accrual and will developand oversee initiatives to increase accrual to thera-peutic clinical trials with a special emphasis onminority accrual. He will continue his academic andclinical positions as a breast and gynecologic cancerradiation oncologist. Lansey, who has extensiveexperience as both an outpatient clinic nurse andclinical trials research nurse has helped direct effortsto improve clinical trials communication, continuityof care, and data management. Overcoming cultural and institutional barriers and

increasing minority participation in clinical trials is apriority of the Kimmel Cancer Center, and Zellars andLansey have a longstanding interest in addressingracial disparities in cancer. Zellars created and co-leads CUPID (Cancer in Under-Privileged Indigent orDisadvantaged), a summer training fellowship aimedat attracting to the specialty oncology medical stu-dents who have a demonstrated interest in caring forpoor and underserved minority populations. •

Edward Allan Sison, M.D., has joined thePediatric Oncology Program as an instruc-tor in oncology and pediatrics. He is aphysician-scientist focused on translationalresearch of childhood leukemia, includingthe development of therapies targetinghigh-risk childhood leukemia.

Katherine Thornton, M.D., has returnedto the Kimmel Cancer Center as the clinicaldirector of the Sibley Medical OncologyProgram. Thornton will be responsible forthe start-up and continuing medical over-sight of the medical oncology consulta-tion/outpatient clinical service at Sibley,which is part of the Washington, D.C.campus of the Kimmel Cancer Center. Shewill also develop and promote clinicalresearch at Sibley, including educationaland training programs for fellows fromJohns Hopkins, the National CancerInstitute, and Howard University.


IN THE NEWSFifteen-year-old Jack Andraka receivedtop honors (the Gordon E. Moore Award)

and a $75,000 prize at the 2012 IntelInternational Scienceand Engineering Fair.Andraka won for hisdevelopment of a newmethod to detect pan-

creatic cancer. Using an approach similarto that of diabetic test strips, the highschool student created a simple dip-sticksensor to test blood or urine for the levelof mesothelin, a pancreatic cancer biomarker. Andraka received guidanceand laboratory space from KimmelCancer Center pancreas cancer researcherAnirban Maitra, M.D.

The 10th annual Avon Walk for BreastCancer was held in Washington, D.C.,

and Johns Hopkinsreceived a grant of$1.3 million grant tohelp the support

the care of women at the Johns HopkinsAvon Breast Center of Excellence.

The St. Baldrick’s Foundation, a volun-teer-driven charity dedicated to raisingmoney for childhood cancer research, hasawarded grants to Colleen Annesley,M.D., for her research on acute myeloidleukemia, and Kathy Ruble, Ph.D., forresearch on the long-term effects of cancer treatment and specifically ways to use physical activity to lower the risk of late health effects.

The inaugural Laura Ziskin Prize intranslational cancer research was awardedto Stephen Baylin, M.D., Ph.D., to studythe epigenetic mechanisms that cancercells use to modify normal gene function.The prize will be shared with Baylin’swife Feyruz V. Rassool, Ph.D., a breastcancer researcher at the University ofMaryland School of Medicine. Ziskin,who died of breast cancer, was co-founderof Stand Up to Cancer.

Jef Boeke, Ph.D., was elected fellow tothe 2012 class of the American Academyof Arts and Sciences, one of the nation’smost prestigious honorary societies and aleading center for independent policyresearch.

The Kimmel Cancer Center recognizedBobbie Burnett and her CaringCollection, which reached a landmarkgoal of more than $1.1 million in donationsto cancer care and research through theproduction and sale of stained glass angels.Burnett was honored with a ceremoniallab coat and Governor’s citation. Thisyear’s Caring Collection donation is sup-porting the research of Chris Gocke, M.D.

Barbara Biedrzycki, Ph.D., R.N.,C.R.N.P., A.O.C.N.P.,was elected to athree-year term as the Oncology Nursing

Society’s (ONS) Directorat Large. ONS is a pro-fessional organizationof more than 35,000registered nurses andhealthcare profession-als dedicated to quality

oncology nursing and cancer care.

Michael Carducci, M.D., and AntonioWolff, M.D., were named 2012Washington, DC-Baltimore-NorthernVirginia Super Doctors. Super Doctors is a listing of physicians from more than40 medical specialties who have attaineda high degree of peer recognition or professional achievement. The listing ispublished as a special supplement in leading newspapers and city and regionalmagazines.

Allen Chen, M.D., was appointed thenew physician advisorfor the Department ofOncology and will leadits Quality and SafetyProgram.

The Giant 8th annual Triple WinnerCampaign raised more than $1.5 millionfor the Kimmel Cancer Center PediatricOncology Program. This adds to the $10million Giant has already donated to ourpediatric cancer program.

Alexandra Gubin, M.S.W., L.G.S.W.,has been named patient navigator for the

Kimmel CancerCenter’s new PediatricOncology Adolescentand Young AdultPatient NavigationProgram. The programwas created in conjunc-

tion with the Ulman Cancer Fund andwill assist teenagers and young adultswith cancer in understanding treatmentoptions through individual and groupsupport and by facilitating connections tofinancial, psychosocial and educationalresources.

Elizabeth Jaffee, M.D., was honored atthe 4th annual Office of Women inScience and Medicine event with the ViceDean’s Award for the Advancement ofWomen. Jaffee was recognized for hergroundbreaking work in science andmedicine.

Richard Jones, M.D. received theLeukemia & Lymphoma SocietyTranslational Research Program Award.

HONORS AND AWARDS


The students at the 2012 AmericanAssociation of CancerResearch/AmericanSociety of ClinicalOncology Methods inClinical CancerResearch workshopselected Judy Karp,

M.D., for the Merrill J. EgorinOutstanding Mentor Award.

The National Comprehensive CancerNetwork (NCCN) Foundation recognizedRonan Kelly, M.D., M.B.A., with itsYoung Investigator Award for researchfocused on assessing or improving outcomes of cancer care.

David Loeb, M.D., Ph.D., was awarded agrant from the Liddy Shriver SarcomaInitiative to support his research of themolecular mechanisms and pharmacolog-ic inhibition of bone sarcoma metastasis.

The Lustgarten Foundation awardednearly $4 million in new research grantsto advance the development of earlydetection and effective treatment optionsfor pancreatic cancer. Johns Hopkinsrecipients were Ana De Jesus-Acosta,M.D., Ralph Hruban, M.D., DanielLaheru, M.D., and Anirban Maitra, M.D.

Maura Kadan, R.N., M.S.N., O.C.N.,Peggy Lang, C.R.N.P., M.S.N., MarianRaben, M.S., PA-C., provided informa-tion on cancer screening, education, clini-cal trials, treatment and cancer care at the2012 B’More Healthy Expo. An estimated20,000 people attended the conventiondesigned to get people moving, takingaction and making choices to be healthier.

Kimmel Cancer Center Director WilliamNelson, M.D., Ph.D., was selected to be aguest on BioCentury as part of a paneldiscussion to explore why collaborativeboundaries need to be reinvented totranslate curiosity-driven science intopatient value. The program spotlights theviews of key scientific opinion leaders,

corporate decision makers, lawmakersand policy architects, venture capitalistsand other investment professionals, andthe patient and consumer groups whostand to benefit most from biotechnology.

Timothy M. Pawlik, M.D., M.P.H., headof the Johns Hopkins Liver TumorCenter, has been appointed the new direc-tor of surgical oncology at the Johns Hopkins University School of Medicine.

Martin Pomper, M.D., Ph.D., and JohnIssacs, Ph.D., each received a ProstateCancer Foundation Challenge Award.They were among nine recipients selectedfrom a pool of 96 applications receivedfrom 10 countries. The awards, a $9 mil-lion investment over a two-year period,are made to accelerate scientific discoveryand new treatments for prostate cancer.

Paul Reed Smith Guitars hosted theacclaimed “One Night, One Show, OneCause,” featuring Journey at the ModellCenter for the Performing Arts at the LyricOpera House. The event raised $250,000 forthe Living with Cancer Resource Programat the Hopkins Kimmel Cancer Center.

As part of its Hyundai Hope on Wheels pro-gram, Hyundai dealers named pediatric oncolo-gist Eric Raabe, M.D., Ph.D., a 2012 HyundaiScholar and presented him with a donation tosupport his brain cancer research.

What is palliative care?I usually tell people that it is hard todefine, but you know it when you see it.In literal terms, it means the managementof symptoms—controlling pain, shortnessof breath, depression, anxiety and thosethings that affect patients’ quality of life.The greatest misperception is that pallia-tive care is only end-of-life care. In fact, itis survivorship care. We now know thatpalliative care is beneficial for all patientswith advanced cancer from the time ofdiagnosis, not just at the end of life. Palliative care was introduced as a

medical specialty in 1990, but just a handful of hospitals offered it. Today, 90 percent have some type of palliativecare program or service.

What caused the big shift?There were a couple of things that hap-pened. First and foremost, we provedthat palliative care had a favorable impacton survival. Two separate studies foundthat patients with advanced cancer whoreceived palliative care lived longer thanpatients who did not. A study of lung cancer patients showed that those whohad palliative care from the onset, usedless chemotherapy at the end of their

lives, spent less time in the hospital, andlived three months longer. The sameresults were seen in other studies. Thesefindings led the American Society ofClinical Oncology to recommend thatevery seriously ill cancer patient get pal-liative care. Secondly, it reduced costs. Effective

symptom management keeps patients outof the hospital, and as a result, there is asignificant cost savings. Managing burgeoning health care

costs, whether we like it or not, is part ofour reality. Insurance premiums for afamily of four have risen from $7,000 toover $15,000 in the last ten years. Patientsare faced with it when they consider

expensive treatments with large copays,and providers of care need to think aboutit too. We simply cannot sustain these rising costs. When we looked at our ownpatients, we found that one-third hadchemotherapy within two weeks of theirdeaths. There is more and more evidencethat this is not helpful, and in fact, it couldbe harmful and actually shorten peoples’lives. More money does not always translate into better care, and by the same token, spending less money does not equate to lesser care. We need to recognize when continuing chemotherapyor radiation therapy is no longer the bestthing for the patient.

What is the Kimmel Cancer Center doingto develop its palliative care program?The first thing we did was to evaluate ourown performance to see where there wasroom for improvement. We have an excel-lent team of palliative care providers thatincludes physicians, social workers, andnurses, but we also recognize there arethings we can do better. For example, Ithink we can do a better job of talking topatients and asking them about theirgoals. Focusing on quality of life is just as important, and sometimes more

important, than focusing on the numberof cancer cells in the body. An American Cancer Society study

found that just one in four cancer patientsfelt they had adequate treatment of theirsymptoms, such as pain and shortness ofbreath. One in three felt they were gettingadequate emotional support, and half saidthey would have benefitted from moreeducation on how to manage pain andcontrol symptoms when they were dis-charged from the hospital. As providersof care, we may think we explain thesethings, but that is not always the patientperception. We have to ask patients: Are you bothered by pain, anxiety, orshortness of breath? What can I help youwith? What did you understand fromwhat we talked about?We have to makesure that we’re not only giving the mes-sage but that our message was receivedand understood by patients and families. Too many patients are dying in the

hospital. It’s not good for them or theirfamilies. They don’t want to be there. Iwould like to see hospice care integratedsooner for patients because patients whohave good palliative care and hospice caretend to live longer. It should be part of thenormal process of care for any patientwho has an advanced cancer that we cannot cure. Then, when a third-linetreatment doesn’t work, patients canmake a smooth transition to this team.

What do you have planned for the painand palliative care program?I would like to see Johns Hopkins whereit rightfully should be, a national leader in palliative care. The Duffey familyshares our vision, and we are fortunatebecause they have provided us ongoingfunding to make this happen. We plan to add doctors and advanced practicenurses to our team. Currently, we have outpatient and inpatient palliative careconsultations. By 2013, we hope also tohave an inpatient unit.We have already established a pallia-

tive care research fellowship and havereceived two research grants. We wouldlike to add a clinical fellowship. We areestablishing and expanding interdiscipli-nary relationships with the School ofPublic Health and the School of Nursingto ensure we are truly providing the bestand most advanced care possible in keeping with the Johns Hopkins tradition.


MEET TOM SMITHTHE BENEFITS OF PALLIATIVE CARETHOMAS J. SMITH, M.D., is one of the world’s leading experts in palliativecare and an accomplished cancer clinician and researcher. He recently joinedthe faculty of the Kimmel Cancer Center as the Harry J. Duffey Family Professorof Palliative Medicine and Director of Palliative Medicine at Johns Hopkins.Smith shared his thoughts on the evolution of palliative care and his goals forthe Kimmel Cancer Center.


Safeway funded pilot breast cancerresearch grants to Leisha Emens M.D.,

Ph.D., EdwardGabrielson,

M.D., Josh Lauring M.D., Ph.D.,Saraswati Sukumar, Ph.D., AntonioWolff, M.D., Luigi Marchionni, M.D.,Ph.D., and Linda Resar, M.D.Also, inhonor of Safeway’s annual campaign tosupport prostate cancer research, KimmelCancer Center Director William Nelson,M.D., Ph.D., and Prostate CancerProgram Co-Director Michael Carducci,M.D., served as guest grocery baggers atone of the store’s Baltimore City locations.

Cynthia Sears, M.D., and Peter Searson,Ph.D., are among the first recipients ofgrants geared to answer “ProvocativeQuestions” in cancer research, a newproject funded by the National CancerInstitute. Grants are aimed at providinganswers to one of 24 questions, solicitedfrom the research community, thataddress neglected or unsolved areas ofcancer research. Sears will explore howand why certain cancers may be causedby infections, and Searson will develop anew method to study how cancer spreads.

C. Michael Armstrong Professor GreggSemenza, M.D., Ph.D., was recognizedfor outstanding professional achievementand commitment to service with his elec-tion into the Institute of Medicine, one ofthe highest honors in the fields of healthand medicine.

The Tigerlily Foundation presented LillieShockney R.N., B.S., M.A.S., with itsInspiration Award. The foundation mis-sion is to educate, advocate, empower andprovide support to young women withbreast cancer.

Donald Small, M.D., Ph.D., received theAlex’s Lemonade Stand FoundationInnovation Award to support his researchof novel treatment for pediatric cancers.

The Tenfold Forty, an organization of 40professional women honored ConnieTrimble, M.D., for her clinical researchin the treatment of HPV-related cervicalcancer with a check to benefit the CervicalDysplasia Center at the Kimmel CancerCenter.

World renowned urologist Patrick C.Walsh, M.D., who pioneered work in theunderstanding and treatment of prostatecancer, was honored with the AmericanAcademy of Arts and Sciences’ presti-gious Francis Amory Prize on March 14.Given by the Academy since 1940, theprize recognizes major advances in repro-ductive biology and medical care.

Bert Vogelstein, M.D., was awarded theAmerican Association of Cancer Research(AACR) Eighth Annual AACR-IrvingWeinstein Foundation DistinguishedLectureship. This Lectureship was established in 2004 to acknowledge anindividual whose outstanding innovationsin science and whose position as a thoughtleader have the potential to inspire creative thinking and new directions incancer research.

The Oncology Nursing Society (ONS) hasawarded Jennifer Wenzel, Ph.D., R.N.,C.C.M., the 2012 Excellence in WritingAward for Qualitative Nursing Research.

Christopher L. Wolfgang, M.D., Ph.D.,was selected to lead the hepatobiliary andpancreas surgery unit, one of two newlycreated sections within the Department of Surgery. Nita Ahuja, M.D., heads the gastrointestinal oncology, breast,melanoma, sarcoma, and endocrine section.

IN THE NEWSHONORS AND AWARDS


ON THE WEB

P&P

ABINGTON HEIGHTS HIGHSCHOOL SCORES WITHRED CARD CANCERAbington Heights High School BoysSoccer Team in Clarks Summit,Pennsylvania continued their supportof Red Card Cancer raising $4,000for the cause. Under the coaching of Steve Klingman, Abington HeightsHigh School has separated themselvesin supporting Red Card Cancer and carrying the message to thecommunity that, “Together We CanMake a Difference.”

YOU’RE BEAUTIFULPatients and staff in the Division ofPediatric Oncology created aYouTube sensation with their video“You’re Beautiful.” Patients, familiesand staff lip sync to the popularBritish boy band One Direction’ssong “What Makes You Beautiful.”One Direction band member LiamPayne is one of the fans. He tweeted about the video.

PHILANTHROPYGIFTS AND DONATIONS to the JOHNS HOPKINS KIMMEL CANCER CENTER


CLINICAL BIOMARKER TESTS FOR CANCERThe Kimmel Cancer Center has becomean incredible engine for biomarker dis-covery and for developing tests and plat-forms to evaluate and assess their benefit.Central to this is a new clinical sequenc-ing laboratory focused on translatinggenetic and epigenetic research and find-ings into clinical tests that will guide can-cer diagnosis, risk stratification, and ther-apy. Clinical experts, laboratory medicineexperts, and genomics experts are work-ing together to figure out how to movethis science and technology forward. Investigators believe that extremes in

patient responses to the same therapycould be rooted in alterations in the can-cer genome and epigenome. Usingsequencing technology to compare thegenetic and epigenetic characteristics ofcancers that responded well to a treat-ment to those that did not, could revealimportant new predictive biomarkers todifferentiate patients who are likely torespond to a particular treatment fromthose patients who will not. The collabo-rative team of clinicians and investigatorswill apply the technology and method totwo cancer types per year to develop an

individualized treatment approach thatcan be studied and validated in large,multi-institutional studies.The team has already begun studies of

prostate cancer, ovarian cancer, and pan-creas cancer to identify the changes thatcause treatment resistance specific to eachcancer as well as those that translate tobetter outcomes. The researchers believethat if they can decipher the molecularcharacteristics that make a seeminglyaggressive and lethal cancer have a long-lasting response to treatment, they canpotentially use drug interventions to convert less responsive tumors and makethem more amenable to treatment. Thesebiomarkers could then be used to guidepersonalized cancer medicine, getting theright treatments to the right patients.

PROVOKING AN IMMUNERESPONSE TO CANCERKimmel Cancer Center cancer immunologyexperts have had breakthrough discover-ies related to an immune inhibitorycheckpoint called PD-1. It is co-opted bytumors to shut down an immune responseto cancer cells. Two clinical trials thatused antibodies to block PD-1 and PD-L1,a related molecule that binds to PD-1,

COMMONWEALTHCANCER SUMMITTHE COMMONWEALTH FOUNDATION for Cancer Research, under the direction ofBoard Chairman William Goodwin, has been a leading supporter of translational, bench-to-bedside research at the Kimmel Cancer Center. After a review of research being con-ducted at cancer centers throughout the country, Goodwin and the CommonwealthFoundation identified the Kimmel Cancer Center and the Memorial Sloan KetteringCancer Center as hotbeds of meaningful research that could be quickly applied to patientcare. Investigators from both centers came together last summer for a cancer summit todiscuss opportunities for collaboration.Promising personalized cancer detection and treatment approaches inspired by

Commonwealth funding include new tests for cancer and vaccines and other cancer-fighting immune strategies.


resulted in significant and long lastingresponses against melanoma skin cancer,renal cell (kidney) cancer, and lung can-cer. The findings in lung cancer wereparticularly significant as it was notthought to be an immune responsive can-cer. Experts say it demonstrates that,with the correct approach, essentially allcancers could be made vulnerable toimmune attacks. This research adds to the growing

body of evidence that the immune systemis not passively tolerant to cancer but thatcancer cells actively hijack immune path-ways to acquire immune resistance. Atumor recognizing it is under attack byimmune cells, up regulates PD-L1 to shutdown the immune response. Conversely,in their studies tumors that did notengage PD-L1 did not respond to treat-ment. The finding opens the door tousing PD-L1 as a predictive biomarker foridentifying patients who will respond toanti-PD-1 therapies, but also as a targetfor combined treatments in patientswhose tumors do not express PD-L1.Vaccines or other immune-targetedapproaches could potentially be used toactivate PD-L1 and prime them for subse-quent anti-PD-1 treatment. The lung can-cer studies, revealed potential synergywith epigenetic-targeted treatments andanti-PD-1 therapy.The anti-PD-1 success has revealed a

need for better ways to monitor these cancers. PD-1 targeted cancers are charac-terized by progression before regressing.Imaging scans, such as CT, for this type oftherapy do not tell investigators what theyneed to know. Researchers are exploringthe possibility of tests that measure tumorDNA in the blood to quantitatively analyzeif the treatment is working. These findings have inspired new col-

laborations funded by the CommonwealthFoundation and Stand Up to Cancer.Investigators believe that PD-1 is just thetip of the iceberg and that there are 10 to 15additional immune checkpoints that arecoordinately and differentially expressedin tumors. They are all potentially targetable with antibodies, molecular pro-files of the tumors could be used to revealthese checkpoints and guide treatment.

NOVEL METHODS OF CANCER DETECTIONThe research team that deciphered the

genetic blueprints for cancer is using theirfindings to develop clinical tests per-formed on routinely collected biologicalfluids, including plasma, sputum, stool,and urine, to detect cancers in an earlyand curable stage and to monitor theeffectiveness of targeted treatments inexisting cancers. The tests in developmentare specific to cancer, have a low rate offalse positives, are cost effective, and highthroughput so they can rapidly processlarge quantities of DNA and informationand be used routinely. The investigatorsenvision such tests, which identify theunique genetic and epigenetic changesthat define cancer, becoming part of a person’s regular physical. These changes are almost always pres-

ent in early cancers, but the challenge isadvancing the sensitivity of the tests todetect a minute amount of cancer DNA cir-culating within a sea of normal cells.Almost all of these changes are presentbefore a cancer spreads, and they are notsimply associated with cancer, as PSA(Prostate Specific Antigen) and othermarkers currently used for cancer detec-tion, they are the cause and driver of can-cer growth and progression. The greatestsuccess has been achieved in tests forcolon cancer and ovarian cancer. Othercancers, such as brain cancers, are prov-ing more difficult. The research team isworking with cancer clinicians to deter-mine the best medium—i.e., plasma, stool,etc.—best suited to the detection of eachspecific cancer. Once the tests are perfect-ed they can be used to monitor people atincreased risk of developing cancer.

PERSONALIZED CELL THERAPYBone marrow transplant and blood andbone marrow cancer experts have devel-oped a personalized treatment approachthat uses patients’ own immune cells tofight their cancer. It focuses on a type of tumor-specific T-cell. For cancers of the blood, these cells, known as marrow infiltrating lymphocytes or MILs, arefound in the bone marrow where the cancer originates.In their normal capacity, the cells are

inactive and somewhat small in numberso they have little effect against the cancer,but our experts are using a clinical con-cept known as adoptive T-cell therapy, inwhich they retrieve a patient’s own MILsfrom his or her bone marrow, grow the

cells in a specialized laboratory to expandtheir numbers and then return them tothe patient where they seek out anddestroy cancer cells. The Kimmel Canceris one of a few cancer centers in the U.S.that perform adoptive T-cell therapy, and,it is the only one using MILs. Currently,the therapy is being studied in multiplemyeloma, an incurable cancer of the bloodplasma cells, but research indicates thatthis personalized cell therapy would bebeneficial in treating a variety of bloodand bone marrow cancers and likely solidtumors as well. Cell therapy is also beingexplored in other medical disciplines,including cardiology.In multiple myeloma, MILs cell therapy

is used in conjunction with bone marrowtransplant to prime antitumor immuneresponse and improve the effectiveness ofthe transplant. Our experts believe thistherapy will improve the duration ofresponses and may one day replace theneed for any additional treatment.

PERSONALIZED PANCREASCANCER VACCINESCancer immunology experts continue tooptimize the effects of the pioneering pancreas cancer vaccine they developedmore than a decade ago. New workincludes the use of peptides to individual-ize vaccines to the unique molecular characteristics of each patient’s cancerand, as a result, improve their responseagainst pancreas cancer. Peptides are the building blocks of

proteins and are a “table of contents” ofsorts displayed on the cell surface toreflect the internal molecular structure of the cell. Vaccines could use peptides toprime immune cells to recognize whensomething is not right within a cell, as incancer. Researchers are studyingwhether identifying peptides that markeach patient’s specific tumor cells andincorporating them in the pancreas cancervaccine could boost the immune responseagainst cancer cells.Other work includes use of multiple

vaccinations to maintain long-termimmune activity against tumor cells.The team’s ultimate goal is to combine

cancer vaccines that target the individualgenetic alterations within the patient’scancer cell with immune modulatingagents that maximize the immuneresponse against the cancer. •


PREVENTING BREASTCANCERTHE JOHN FETTING FUND FORBREAST CANCER PREVENTION“Our goal should be to do more than curebreast cancer. We must prevent it,” JohnFetting told a group of people who came

to the Kimmel CancerCenter to learn aboutthe Fetting Fund forBreast CancerPrevention. Fetting, abreast cancer clinicianfor more than three

decades believes that recent researchbreakthroughs about the biology of breastcancer can now be applied to prevent itfrom occurring at all.“Over the course of my career, I’ve

seen substantial progress made againstbreast cancer, and I’m very gratified bythat,” says Fetting. “Screening mammog-raphy has led to earlier diagnosis, andtreatments have become more effective, somore patients are surviving and living fulllives. Still, I think we can do better. Withthe same kind of concerted effort that hasbeen mounted to cure breast cancer, wecan prevent it from ever occurring.”After battling breast cancer herself,

Leslie Ries became a proponent of preven-tion. “Advances in treatment options are

not enough. We have totry to protect ourselves,our children, and oth-ers from getting thisdisease,” says Ries whohelped to establish theFetting Fund with her

husband Tom to allow laboratory discov-eries to be translated into preventionstrategies. To date, with a lead gift addedby Lorraine and Mark Schapiro, $1 millionhas been raised toward the cause. Fettingtreated the Schapiros’ daughter. “He wasfabulous, but I wish we never had to gothrough this,” says Mrs. Schapiro.“Prevention is better than a cure, and weneed to start moving in that direction.”Fetting says that discoveries made at

the Kimmel Cancer Center that reveal thegenetic (mutations to DNA) and epigenetic(nonmutational alterations to DNA)

(SAA) Baltimore event has raised morethan $1 million for the Kimmel CancerCenter creating the Swim Across AmericaLaboratory at Johns Hopkins directed bygastrointestinal cancer physician-scientistLuis Diaz, M.D. The money is helpingDiaz and his team develop gene-basedtests that can detect cancer, monitor itsprogression, and pinpoint the best treat-ments. “We have made a lot of progresswith the Swim Across America donations.We are applying it to research againstcancers that are hard to treat and wherethere are currently no standard therapiesthat are curative,” says Diaz. “This sup-port makes it possible for us to take thebest ideas and bring them to patients.” Swim Across America funds also sup-

port a number of patient-directed initia-tives including new clinical trials for tar-geting pancreatic cancer and advancedcolon cancer; a survivorship clinic forcolon cancer patients who have finishedtreatment; and a special three-day couplesretreat for colon cancer patients withadvanced disease and their caregivers.Hundreds of swimmers took to the

water at Meadowbrook Aquatic Center inBaltimore and the Waltjen-Shedlick Farmnear Gibson Island on September 23 forthe 2012 event. As in the previous twoyears, a number of current and formerOlympic swimmers joined the pool andopen water events including Brad Snyderand Ian Silverman (both gold medalists atthe 2012 London Paralympics), CraigBeardsley, Brenda Bartlett, Wendy Weiland Tara Kirk Sell. During their time inBaltimore they also stopped by the KimmelCancer Center to visit children with cancerand their families. This year’s event also included a special

tribute to Alec Cosgarea. Seventeen-year-old Alec was a world-class swimmer andSwim Across America veteran who organ-ized “angel swimmers” matching accom-plished swimmers like himself with noviceparticipants as companions for the openwater swim. Tragically, Alec was killedjust months before the event in an automo-bile accident, but his spirit was an unmis-takable and powerful part of the day’sevent. Many thousands of dollars were

PHILANTHROPY

Fetting

Ries

changes that cause breast cancer can beused to better distinguish those women atrisk for breast cancer so that clinicianscan intervene early before the cancer cancause her harm. “One in nine women willbe diagnosed with breast cancer, “ saysFetting. “That means one will get breastcancer but eight will not. We need toadvance our science so that we can identi-fy ‘the one’ and intervene to prevent breastcancer. We also need to use this science toidentify and reassure the eight who willnot,” he says. “A normal cell does notbecome a breast cancer overnight,” saysFetting. “It happens over many years, sowe can look for this genetic and epigeneticsignature of breast cancer and figure outwho has these changes and who does not.”Kimmel Cancer Center breast cancer

experts are examining several ways tointerfere with the biological changes thatset breast cancer in motion. Breast cancerexperts are investigating the protectiveeffects of certain natural chemicals foundin fruits and vegetables and figuring outhow best to deliver them to individuals.They also are studying ways to halt themolecular and cellular changes that trig-ger breast cancer with drugs that reactivatekey tumor suppressor genes that had beenturned off through epigenetic alterations. Leading cancer experts agree that pre-

vention is one of the best ways to managecancer risk, however, it is an area of can-cer research that is currently underfund-ed. “The Fetting Fund will support thistype of work so that we can begin toreplace fear with hope,” says Ries,“because we all deserve a future withoutbreast cancer.”For more information on the Fetting Fund

for Breast Cancer Prevention or to make acontribution, contact Dina Klicos at 410-516-4203 or [email protected]

SWIM ACROSSAMERICA

MAKINGWAVES TOFIGHT CANCEROver the last threeyears, the SwimAcross America


raised in his memory, and SAA Baltimoreestablished the Alec Cosgarea Award forthe top fund raiser under 18 years old.“Alec was all about caring for other peo-ple,” said Eric Posegay, high performancecoach at Meadowbrook. Alec’s fatherAndy Cosgarea, a Johns Hopkins orthope-dic surgeon, took his son’s place in thewater, and his younger brother Will organ-ized this year’s “angel swimmers.” Diaz also was among the swimmers.

“I am so proud of Baltimore. The supportof our community is not only motivatingto the clinicians and researchers but topatients as well,” says Diaz. “It means alot to them to know their community isbehind them.”

AN EXAMPLE OF WHERESAA MONEY GOESUNMASKING CANCER’S HIDDEN DEFENSESIt is perhaps the most challenging andfrustrating aspect of cancer therapy, fordoctors and patients alike. A treatmentworks; the cancer shrinks, and then sud-denly the treatment is no longer effective,and the cancer returns with a vengeance.New findings from Swim Across Americaand Ludwig Center researchers havebegun to unravel what happens withinthe cancer cell to cause its resistance totreatment. In fact, their research finds, theorigins of the cancer treatment resistancewere hidden in the cancer cell all along. Personalized therapies involve drugs

that target specific gene alterations within

a patient’s cancer. Clinicians decidewhich drugs will work against the cancerbased on the alterations they find insidethe cells’ DNA. Cancer is generally characterized by a

combination of tumor cell-suppressinggenes being turned off and growth-pro-moting oncogenes getting turned on.Each person’s cancer has a unique combi-nation of these molecular mistakes con-tained within the sequestered DNA of thecancer cell. This genetic fingerprint helpsdetermine which drugs are likely to workagainst the cancer and which ones will not. When a treatment does not work,

resistance mutations are often the cause.A cancer cell is, after all, a normal cell thathas errantly acquired genetic traits thatallow it to grow immortally and uncontrol-lably. Resistance mutations occur amongthese alterations and they add up over timeas cancer cells divide and grow. “Tumorsalways contain thousands of resistancecells,” says Luis Diaz, director of theKimmel Cancer Center Swim AcrossAmerica Laboratory. The more advanced acancer is, the more resistance alterations itacquires, giving the cells that contain thema greater chance to survive treatment. Diaz worked with leading cancer

genetics researchers Bert Vogelstein andKenneth Kinzler, co-directors of theLudwig Center for Cancer Genetics andTherapeutics, to better decipher andunderstand the molecular origins of tar-geted therapy resistance. The team analyzed blood samples from

28 patients with advanced colorectal can-cer who were being treated with a drugthat targets an important tumor cellgrowth pathway known as EGFR. Patientsmost likely to respond to the targeted agenthave normal copies of the cell-growth-promoting oncogene known as KRAS.Among the study group, only fourpatients tested positive for mutations ofthe KRAS gene. Researchers would notexpect them to respond to the treatment,but the remaining 24 should have benefit-ed. So why have so many of thesepatients relapsed? The answer, Diaz,Vogelstein, and Kinzler found, was thereall along. The resistance mutations werealready there. They were simply unde-tectable until the tumor grew. As cancer cells multiply, they shed

DNA into the blood and reveal the geneticmutations contained in the cell. The morecancer cells there are, the more DNA thatis shed. Diaz, Vogelstein, and Kinzlerhave lead the world in developing bloodand other tests that pluck this obscuredDNA from within a sea of normal cells.They used this technology to periodicallylook for cancer DNA in simple blood sam-ples obtained from the patients. Five toseven months into treatment, their testrevealed that nine of the patients whobegan treatment with normal KRAS genes,now had KRAS mutations. This molecularevidence foretold that the cancers wouldcontinue to grown even before the advanc-ing disease could be detected in imagingscans, but when did these mutations occur? The team called upon the mathemati-

cal expertise of Harvard University col-league Martin Nowak who developed amathematical model to date these alter-ations. He found that KRAS mutationswere present, just undetectable, before thepatients even began their targeted treat-ment. Although the studies were in colon

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(Left to right) WilliamNelson, Debbie Dawson, Kay Foley, and Luis Diaz


cancer, Vogelstein says the findings likelyapply to all targeted therapies. “Thismeans that the development of drugresistance with single-agent targeted therapies is a fait accompli,” Vogelsteinconcluded. “Long-term remissions ofadvanced cancers will be nearly impossiblewith single targeted agents.” It’s reallyjust a matter of when they will recur. That,he says, simply depends on how long ittakes cancer cells with the mutant genesto multiply.”This latest research adds to thebuilding body of evidence that metastaticcancers will be nearly impossible to con-trol. The ideal opportunity to cure cancerlies in detecting it early when tumors aresmall and have fewer resistance genes orcan be removed with surgery.Multi-drug and method combinations

that simultaneously attack a variety ofgenetic cancer drivers or reactivatesilenced tumor suppressor genes are abetter option, and Vogelstein is calling fora change in how the cancer world con-ducts early clinical trials whose partici-pants are almost always patients withadvanced cancers. “Since we know thatsingle agents will not have long-term suc-cess, we need to start testing new drugs ascombination therapies much earlier,” hesays. “There are a limited number of genesignaling pathways that go awry in cancer,so it should be possible to develop a smallnumber of agents that can be used in alarge number of patients.”In addition, Director William Nelson,

wants to begin using the Kimmel CancerCenter’s clear edge in cancer genetics dis-covery and application to develop screen-ing tests that would detect cancers whenthey are very new and before they causeany symptoms. “We need to move awayfrom a system in which we see patientsfor the first time when they begin experi-encing symptoms to one that detect, man-ages, and eradicates cancers before peopleeven know they have them,” says Nelson.“Imagine, for example, if we could find

cancers early enough that we could burnthem off much like we do with a wart,”says Nelson. “I think this is within therealm of possibility, and I think our

Center is uniquely positioned to make ithappen.” He points to colonoscopy. It isa screening test that, when performedcorrectly, detects precancerous polyps inthe colon that can be removed during thescreening to prevent a colon cancer fromever occurring. “We need similar types ofstrategies for all cancers,” says Nelson.Once these techniques are developed,

the challenge then is not to overdetect andovertreat cancers, and this is where heagain believes Kimmel Cancer Center science can inform. The same moleculargenetic information that is being used topersonalize cancer treatments can be usedto personalize cancer screening and detec-tion. Rather than a one-size-fits-all,Nelson says the frequency and intervalsof cancer screening can be determined bylooking at the cellular cues. It will pointus toward abnormal cells, like polyps, but also tell us which ones need attentionand which ones can be left alone. The endresult, says Nelson, is that that we willnot only improve cancer outcomes, butalso reduce the adverse affects that comewith overscreening and overtreating. Hesays, “We will be able to preserve healthby preventing cancer, very accurately pre-dict who will get cancer, and personalizetreatments to get the right treatments topatients who need them and spare thosewho will not benefit.”

INNOVATIVE RESEARCHBrian Ladle, M.D., is the 2012 OptimistFellow at Johns Hopkins. His researchfocuses on immunotherapy and novelnew therapies that trigger the body's own

immune system to recognize and attackcancer cells, just as theydo bacteria, viruses,and other foreigninvaders. Since cancercells arise from normal

cells, they most often go undetected by theimmune system, but Johns Hopkinsinvestigators have been on the cuttingedge deciphering the mechanisms bywhich immune cells are activated, andplan to apply this new knowledge to inno-

vative therapeutics. The immune system,much like cancer, is quite complex.Applying immunology to cancer patientsis more difficult still as their immune sys-tems have already been compromised bythe drugs used to treat cancer. Dr. Ladlewill be working with other senior investi-gators to uncover chinks in the immunesystem’s armor that will allow them toturn off the defense mechanism of tumorsand ramp up the immune system’s attackagainst them.

OPTIMIST INTERNATIONALHELPING TO UNLOCK THEMYSTERIES OF PEDIATRIC CANCEROptimist International has been a vitalpartner to Johns Hopkins PediatricOncology in its fight against childhoodcancer. A $1 million legacy endowmenthas helped our clinician-scientists realize

breakthroughdiscoveries. Thesuccess of thispartnership isbest reflected inthe lives of themany children

who have benefitted from innovativetherapies developed by our OptimistFellows. For the first time in the historyof cancer medicine, the technology existsto quickly decipher the cellular causes ofevery cancer. Kimmel Cancer Centerresearchers have pioneered the sciencethat has led us here and were the first tocrack the genetic code of a pediatric cancer.What we have learned is now allowing ourscientists to target the very biologicalmechanisms that cause a cancer to growand spread. With these discoveries, theycan begin to alter the course of pediatriccancers in ways that could only be imag-ined a decade ago. Optimist International has generously

made an additional commitment to make sure we get there. The OptimistInternational Innovative Research Fundwill allow us to significantly expand ourclinical and research programs in child-hood leukemia, pediatric brain tumors,sarcomas and other solid tumors, andbone marrow transplantation.

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