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Center for Hematology and Oncology Molecular TherapeuticsResearch at the Taussig Cancer Center

clevelandclinic.org/cancer

Cleveland Clinic is at the forefront of the cancer drug

discovery and development revolution. We have

identified new molecules with anti-tumor effects,

developed collaborative ties with biotechnology

companies, begun training more young scientists,

and expanded our base of financial support. These

bold steps will result in discovery and application

of new therapies to help us eliminate cancer as a

significant cause of mortality.

Principal Investigators:

Ernest C. Borden, M.D. Daniel J. Lindner, M.D., Ph.D. Pierre L. Triozzi, M.D.

Jaroslaw P. Maciejewski, Ram Ganapathi, Ph.D. M.D., Ph.D.

CONTENTS

01 Introduction

03 DrugDiscoveryand

Development

05 BordenLaboratory

07 LindnerLaboratory

09 TriozziLaboratory

11 ExperimentalHematology

andHematopoiesis

13 ClinicalPharmacology-

ExperimentalTherapeutics

As a result of our improved understanding of the human genome and its significance for cancerbiology,wehavefoundabnormalitieswithinthemalignantcellthatpresentmoretargetsforwhichnewdrugsanddiagnosticscanbedeveloped.

InvestigatorswithintheCenterforHematologyOncologyMolecularTherapeutics(CHOMT)and the Taussig Cancer Center will continue to translate these findings into bedside applications.Theultimateresultwillbeahighercurerateforcancerand,itishoped,fewertreatmentsideeffects.

TheuniquefeatureofCHOMTisitsintimaterelationshipwiththephysiciansandsupportstaffof the Taussig Cancer Center, which facilitates the delivery of “first in man” studies and the translationofideasfromthelaboratorytotheclinic.

DerekRaghavan,M.D.,Ph.D.,FACPM. Frank & Margaret Domiter Rudy Distinguished Chair; Director, Taussig Cancer Center; Chairman, Cancer Division, Cleveland Clinic

From the Director

Cleveland Clinic Taussig Cancer Center Center for Hematology and Oncology Molecular Therapeutics

Taussig Joins Case Comprehensive Cancer Center

In 2004, the Taussig Cancer Center finalized a partnership with Ireland

CancerCenterandCaseWesternReserveUniversitytoformathirdpartof

theNCI-designatedCaseComprehensiveCancerCenter.Thispartnership

strengthenedthetechnologiesforbasicresearch,increasedcollaborative

researchopportunities,facilitatedanenlargedclinicaltrialsprogram,and

enhancedexternalfundingopportunities.Anotherimportantpartnerindrug

discoveryanddevelopmentinitiativesistheClevelandClinicLernerResearch

Institutewhosescientistsworkonmanycommonandcomplementary

projectswiththeinvestigatorsatTaussig.

clevelandclinic.org/cancer 1

The Center for Hematology and Oncology Molecular Therapeutics (CHOMT)wasformedin2005,spurred

by a surge in both human and financial resources for therapeutic and diagnostic bench research on new

therapeuticsandtheirtargets.TheCentercomprisessixresearchlaboratoriesfocusingondrugdiscovery

anddevelopment,clinicalpharmacologyandexperimentaltherapeutics,andexperimentalhematology

andhematopoiesis.

Designedasapremiertranslationalmolecularresearchunit,CHOMT will enhance the scientific and academic

statureoftheClevelandClinicTaussigCancerCenter,produceanewgenerationofphysicianscientistsand

augmentavailabilityofnewdiagnosticandtherapeuticmodalitiesforourpatients.

Withintheirindividuallaboratories,CHOMTinvestigatorsarefocusedonbuildingupontheremarkableadvances

inmolecularbiologicaltechniquesofthelast30years.Theseadvancesarebeingappliedtonewpharmaco-

logical,immunological,biologicalandcellularapproachestotherapeuticsanddiagnostics.Togetherwiththeir

colleaguesatLernerResearchInstitute,particularlyinthedepartmentsofCancerBiology,CellBiology,

ImmunologyandMolecularBiologyandGenetics,newtherapeuticanddiagnosticapproachesbased

on targeting specific genes and gene products are emerging into preclinical and clinical development.

Frominception,thestrategicapproachofresearchprogramswithintheTaussigCancerCenterlaboratoriesis

the translation of research findings from bench to clinic and the pursuit of clinical observations at the bench.

Research on new drugs and diagnostics targeted at defined molecular structures will continue to increase both

qualityoflifeandlengthoflifeforpatients.Ourvisionistocreateanenvironmentofscholarshipforadvancing

knowledgetowardcurativetreatmentforourpatients.Thefollowingareexamplesofourresearchactivities

and advancements as we work to discover and translate laboratory findings into clinical trials and, ultimately,

reducecancermorbidityandmortality.WearepositioningCHOMTtobecomeoneofthemajorcentersinthe

worldforresearchonbiologicallytargetedtherapeutics.

Inaddition,ClevelandClinicparticipatesintheSouthwestOncologyGroup,RadiationTherapyOncologyGroup,

Children’sOncologyGroup,Blood-BrainBarrierConsortium,NewApproachestoBrainTumorTherapyandthe

GynecologicOncologyGroup.Throughphysicianparticipation,cancerpatientshaveaccesstoavarietyof

clinicaltrialsinvestigatingnoveltherapeutics.

Introduction


Collaboration


Drug Discovery and Development

CHOMTwasanaturaloutgrowthoftheCenterforCancerDrugDiscoveryandDevelopment,foundedin1998

attheTaussigCancerCenter.Itenlargedourscopeofactivitiestobuildforthefuturebutremainsfocusedon

asimplemission:tobringcancerpatientsnew,novelandeffectivedrugsforcancertreatment.Theintentis

todiscoveranddeveloptherapeuticswithaparticularfocusonbiologicalagentstargetedatgenesorgene

productsthatdeterminethecourseofcancerdevelopment.Weaimtotranslateinnovativeapproachesinto

rigorousclinicaltrials,thusofferingphysiciansnewmethodsofcombatingcancer.Thecenterprovidesafocus

forinvestigationofnewmoleculesinpreclinicalscreeningsystemsandtotranslatetheinformationaboutnovel

cancer-relatedmoleculestoclinicaltrials.Byusingtheprinciplesofpharmacologyandtheknowledgeofcancer

biology,wedesignanddevelopnewcompoundsorcombinationsofnewbiologicallytargetedcompoundsthat

willreducemorbidityfromoldertreatmentsandreduceboththecomplicationsandmortalityfromcancer.

Someofthesemoleculeshavealreadyprogressedintoclinicaltrialsinourambulatoryclinicsandatthe

NIH-fundedGeneralClinicalResearchCenteratClevelandClinic.

Weuseinnovativebiostatisticalmethodologiestoexpediteevaluationofdrugtherapies.Oureffortsinclude

thedevelopmentofonlinenetworkstoacquireclinicaldataforrapid,comprehensiveanalysis.Collaborationis

key.InadditiontothoseatLernerResearchInstituteandCaseComprehensiveCancerCenter,preclinicaland

clinicalresearchonnewmoleculesisunderwayinassociationwithorganizationsandcompaniesinChina,

Switzerland,IsraelandacrosstheU.S.These,andcollaborationswithbiotechnologycompaniesinCleveland

andacrosstheU.S.providenewdrugsthatinhibittumorcellgrowth.Thus,asadvancesfromCHOMTare

ready for the more advanced stages of clinical trials, Phase II and Phase III, a rapid and efficient process can

be initiated for the final steps in bringing new drugs to patients. Our objectives are to develop innovative drug

screeningtechnologieswhilecontinuingourresearchinthedesignofsmallmoleculestargetedatcellular

signaltransduction.Weaimtousenormalprogrammedcelldeath(apoptosis)asameansbywhichtocurtail

tumor development through induction of identified genes. Over the next few years, new investigators will be

recruitedforCHOMTtoaddtoexistingexpertise.

Linkingresearchtocure,thecenteriscontributingtotheemergenceoftheTaussigCancerCenterasoneof

theleadingcancerresearchcentersinthecountry.

Collaboration


Evolution

CTscansofapatientwithmetastaticrenalcarcinomasuccess-

fullytreatedattheTaussigCancerCenterwithanewtypeof

interferonbeinginvestigatedinCHOMTlaboratories.(A)Chest

CTatbaselinedemonstratingrightupperlobepulmonary

metastasis.(B)RepeatCTshowingnearresolutionofmetastatic

lesion.(C)AbdominalCTatbaselinedemonstratingtense

ascites.(D)AbdominalCTafter12weeksoftherapyshowing

reductioninascites.Inadditiontotumorresponse,studies

demonstrateincreasedinterferon-stimulatedgenesandbetter

patienttolerancewiththistypeofinterferon.Theresearchisa

collaborativeeffortbetweentheMinistryofHealthinShanghai,

whichproducestheinterferonbyrecombinantDNAtechnology,

andCHOMT,conductedasanFDA-approvedinvestigationaltrial.

A B C D


Interferons(IFNs)haveprovenanimportantparadigmforestablishingtheroleofbiologicalsaseffective

therapyinhumanmalignancies.IFNsarepossiblythemostpotentmodulatorsofgeneexpressionusedin

clinical medicine. Through gene profiling, our laboratory and others have identified over 300 IFN-stimulated

genes that influence apoptosis, immune responses and angiogenesis, and are induced in expression by IFNs.

These newly identified genes may be particularly critical in mediating the anti-tumor effects of not only IFNs but

alsoothercancertherapeutics.Asaresultofgenemodulation,IFNsareaprototypefortherapeuticsthatwork

throughregulationofcellularsignalingpathways.Despitesubstantialprogress,westilldonotunderstandthe

underlyingmechanismsoftumorsensitivityandresistance.HowtoovercomeresistancetoIFNsandother

cytokinesinnon-respondingpatientswithmelanomaandothermalignancieshasbeenlittleexplored.

Our goal is to define defects in expression or activation of signal transduction components and extend our studies

ofinterventionstocorrectabnormalities.TheseincludestudiesofreversalofsilencingofIFN-stimulatedgenesby

methylationoftumorDNAandtoenhancetheeffectivenessofIFN-stimulatedgenesbyinhibitionofsignaling

phosphatases.Todetermineeffectivenessoftheseapproaches,inadditiontostudiesatthelaboratorybench,we

areassessingIFN-stimulatedgenesinpatientsreceivingIFNsandotherbiologicallytargetedtherapeutics.We

anticipatethatthesestudieswilltranslateintomoreeffectivetherapieswithIFNsandothercytokines.

Borden LaboratoryPrincipal Investigator: Ernest C. Borden, M.D.

Malahov MP, Kim K, Malakhova OA, Jacobs BS, Borden EC,ZhangD.High-throughputimmunoblotting-ubiquitin-likeproteinISG15 modifies key regulators of signal transduction. J Biol Chem. 2003;278:16608-16613.

Leaman DW, Ozdemir A, Chawla-Sarkar M, Borden EC. Novelgrowthanddeath-relatedIFNstimulatedgenes(ISGs)inmelano-ma:GreaterpotencyofIFN-betacomparedtoIFN-alpha.JInter-feron&CytokineRes.2003;23:745-756.

Chawla-SarkarM,BaeSI,ReuFJ,JacobsBS,LindnerDJ,BordenEC.Down-regulationofBcl-2,FLIP,orIAPs(XIAPandsurvivin)bysiRNAs sensitizes resistantmelanomacells toApo2L/TRAIL-in-ducedapoptosis.CellDeathDiffer.2004;11:915-923.

WengDE,MasciPA,RadkaSF,JacksonTE,WeissPA,GanapathiR,ElsonP,CapraWB,ParkerVP,SandbergJA,CowensJW,Us-manN,BordenEC.AphaseIclinicaltrialofaribozyme-basedangiogenesisinhibitortargetingVEGFR-1forpatientswithrefrac-torysolidtumors.MolCancerTher.2004;4:948-955.

RohatinerAZS,GregoryWM,PetersonB(CALGB+ECOG),Bor-denE (ECOG),Solal-CelignyP (GELA),HagenbeekA (EORTC),Fisher RI (SWOG), Unterhalt M (GLSG), Arranz R (LNH-PRO),ChisesiT,AvilesA,ListerTA.Ameta-analysistoevaluatetheroleof interferon (IFN-a2) in follicular lymphoma. J Clin Oncol.2005;23:2215-2223.

ReuFJ,LeamanDW,MaitraRR,BaeSI,CherkasskyL,FoxMW,RempinskiDR,BeaulieuN,MacLeodAR,BordenEC.ExpressionofRASSF1A,anepigeneticallysilencedtumorsuppressor,over-comes resistance to apoptosis induction by interferons. CancerRes.2006;66:2785-2793.

FanK,ZhouM,PathakMK,LindnerDJ,BordenEC,YiT.SodiumstibogluconateinteractswithIL-2inanti-RencatumoractionviaaTcell-dependentmechanisminconnectionwithinductionoftu-mor-infiltrating macrophages. J Immun. 2005;175:7003-7008.

Publications:


ImaginationDrs.JosephBauerandDanielLindnerwererecentlyawardedanNIHRAID(RapidApplicationtoInterventionDevelopment)awardtofurtherthepreclinicaldevelopmentofnitrosylcobalamin(NO-Cbl).


Abetterunderstandingofhowinterferons(IFNs)induceapoptosismayallowtheirimprovedclinicalutilization

asanti-tumoragents.IFNsinducecytotoxicityinseveraltumorcelllinesincultureandinvivo.Themechanism

bywhichthisoccursrequiresthefunctionofIFN-inducedgeneproducts.Toidentifyfunctionallyrelevant

death-associatedgeneproducts,thislaboratoryhasemployedanantisensetechnicalknockoutstrategy.

In this approach, specific death-inducing genes, termed Regulators of Interferon-induced Death (RIDs)

areinactivatedbyantisensegeneproducts,thusprovidingagrowthadvantagetotransfectedcellsinthe

presenceofIFNs.Currently,wearestudyingoneofthesegenes,inositolhexakisphosphatekinase2,to

determinehowitpromotesappoptosis.

In order to potentiate their clinical efficacy, IFNs are increasingly being utilized in combination therapy. In col-

laborationwithDr.ErnestBorden’slaboratory,ourresearchhasshownthatcombinationofIFNswithanti-es-

trogenssuchastamoxifenorwithretinoidssuchasall-transretinoicacidresultsinenhancedanti-tumoreffects,

bothincellcultureandinxenograftmodels.Partoftheincreasedanti-tumoractivityisduetodirectanti-cellular

effectsmediatedbythedrugcombination,andaportionoftheanti-tumoreffectissecondarytoenhancedhost

effects.Oneofthemostimportantanti-tumoreffectsmediatedbyIFNsistheinhibitionoftumor-inducedangio-

genesis.Onamolarbasis,IFNsarethemostpowerfulanti-angiogenicagentscurrentlyknown.

Ourlaboratoryisalsoactiveintheareaofcancerdrugdevelopment.Dr.JosephBauerhassynthesizedanovel

chemotherapeuticcompound,nitrosylcobalamin(NO-Cbl),thatconsistsofnitricoxideboundtovitaminB12.

NO-Cbl acts as a “Trojan Horse,” and we believe this approach may target tumors through their high require-

mentforvitaminB12.TherecentRAIDawardfromNIHwillmoveNO-CbIrapidlytowardclinicaldevelopment.

Lindner LaboratoryPrincipal Investigator: Daniel J. Lindner, M.D., Ph.D.

Lindner,DJ,TaylorKL,ReuF,MasciP,BordenEC.Interferons.InBAChabnerandDLLongo,eds.CancerChemotherapyandBiotherapy.Philadelphia:Lippencott-RavenPress,2005.

Morrison,BH,TangZ,JacobsBS,BauerJA,LindnerDJ.Apo2L/TRAIL induction and nuclear translocation of inositol hexaki-sphosphatekinase2duringIFN-beta-inducedapoptosisinovar-iancarcinoma.BiochemJ.2005;385:595-603.

Chawla-Sarkar,M,BaeSI,ReuFJ,JacobsBS,LindnerDJ,Bor-denEC.DownregulationofBcl-2,FLIPorIAPs(XIAPandsur-vivin)bysiRNAssensitizesresistantmelanomacellstoApo2L/TRAIL-inducedapoptosis.CellDeathDiffer.2004;11:915-923.

Whitmore,MM,DeVeerMJ,EdlingA,OatesRK,SimonsB,Lind-nerDJ,WilliamsBR.Synergisticactivationof innate immunityby double-stranded RNA and CpG DNA promotes enhancedanti-tumoractivity.CancerRes.2004;64:5850-5860.

Markman, M, Belinson J, Webster K, Zanotti K, Morrison B,JacobsB,BordenEC,LindnerDJ.Phase2 trial of interferon-Betaassecond-linetreatmentofovariancancer,fallopiantubecancer, or primary carcinoma of the peritoneum. Oncol.2004;66:343-346.

Chawla-Sarkar,M,BauerJA,LupicaJA,MorrisonBH,TangZ,Oates RK, Almasan A, DiDonato JA, Borden EC, Lindner DJ.

SuppressionofNF-kappaBsurvivalsignalingbynitrosylcobala-min sensitizes neoplasms to the anti-tumor effects of Apo2L/TRAIL.JBiolChem.2003;278:39461-39469.

Chawla-Sarkar, M, Lindner DJ, Liu YF, Williams BR, Sen GC,Silverman RH, Borden EC. Apoptosis and interferons: Role ofinterferon-stimulatedgenesasmediatorsofapoptosis(review).Apoptosis.2003;8:237-249.

BauerJA,MorrisonBH,GraneRW,JacobsBS,BordenEC,andLindnerDJ. Interferonalpha2band thalidomide synergisticallyinhibittumor-inducedangiogenesis.JInterferon&CytokineRes.2003;23:3-10.

BauerJA,BHMorrison,RWGrane,BSJacobs,DabneyS,Gam-ero A, Carnevale KA, Smith DJ, Drazba J, Seetharam B, andLindnerDJ.Effectsof interferonbetaon transcobalamin II-re-ceptorexpressionandantitumoractivityofnitrosylocbalamin.JNatlCancerInst.2002;94:1010-1019.

Lindner, DJ. Interferons as antiangiogenic agents. Curr OncolRep.2002;4:510-514.

Pathak,MK,DhawanD,LindnerDJ,BordenEC,FarverC,andYiT.PentamidineisaninhibitorofPRLphosphataseswithanti-canceractivity.MolCancerTher.2002;1:1255-1264.

Publications:


Progress


Vaccineshavebeenanattractiveandaggressivelypursuedapproachtothemanagementofcancer.Anumber

ofvaccineshavebeenshowntogenerateimmuneresponsesincancerpatients.Todate,however,therehas

beenlittleevidenceofclinicalactivity.Amajorproblemisthatantigensexpressedbytumorsarepoorimmuno-

gens. Whereas viral antigens are “foreign” and highly immunogenic, tumor antigens are “self antigens,” for

whichahighdegreeofimmunologictoleranceexists.Itisalsobecomingincreasinglyapparentthattumors

canexpresspropertiesthatenablethemtoescapeimmuneresponses.Thislaboratory’sresearch,which

involvespreclinicallaboratorystudiesinanimalmodelsandclinicaltrialsincancerpatients,hasfocused

onhowtoimprovetheabilitytobreaktoleranceanddealwithtumorescapephenomena.

Anincreasingbodyofevidenceindicatesthatwhetherornotimmunetoleranceisbrokenandanti-tumor

Tcellresponsesareeffectivelygenerateddependsonthefunctionofdendriticcells,widelydistributed

antigen-presenting cells that are far more efficient than other antigen-presenting cells in stimulating critical

cellularimmuneresponses.Thislaboratoryisexaminingmethodsofstudyingdendriticcellsubpopulations

andmethodsoftargetingandactivatingdendriticcellsinpatientswithcancer.Thelaboratoryisusinga

novelassaytoidentifyactivatedcirculatingdendriticcells,acellulartargetforCSF-GMfunctionthatleads

toenhancedimmunerecognition.Clinicaltrialsapplyingnovelmethodsofassessingdendriticcellfunction

areinprogressinpatientswithprostatecancer.

Cancervaccinesmimickingvirusesmayprovetobeaneffectiveapproachtobreakingtolerance.Thislaboratory

isstudyingrecombinantviralvectorsencodingfull-lengthtumorantigenstoexploittheinherentimmunogenicity

ofthevirusaswellastheendogenousprocessingandpresentationofseveraltumorantigens.Ourresearchers

alsohavebeenevaluatingtheuseofanon-pathogenicvirus,adeno-associatedvirus,asavaccinevector.

Preclinicalstudiestargetingcarcinoembryonicantigeninmodelsofcoloncancerareinprogress.

Triozzi LaboratoryPrincipal Investigator: Pierre L. Triozzi, M.D.

TriozziPL,KhurramR,AldrichA,WalkerMJ,KimJ,andJaynesS.Intratumoralinjectionofdendriticcellsderivedinvitroinpa-tientswithmetastaticcancer.Cancer,89:2646-2654,2000.

MoultonHM,YoshiharaPH,MasonDH,IversenPL,TriozziPL.Active specific immunotherapy with a ß-human chorionic gona-dotropinpeptidevaccine inpatientswithmetastaticcolorectalcancer:Antibodyresponseisassociatedwithimprovedsurvival.Clin Cancer Res,8:2044-51,2002.

PonnazhaganS,MahendraG,LimaJ,AldrichW,JenkinsC,RenC,KallmanL,StrongTV,ShawDR,TriozziPL.Augmentationofanti-tumoractivityofarecombinantadeno-associatedviruscar-cinoembryonic antigen vaccine with plasmid adjuvants. Hum Gene Ther,15:856-64,2004.

PereboevAV,NagleJM,ShakhmatovMA,TriozziPL,CurielDT,Blackwell JL. Enhanced gene transfer to mouse dendritic cellusingadenoviralvectorscoatedwithanoveladaptermolecule.Molecular Therapy,9:712-720,2004

TriozziPL,BolgerGB,NeidhartJ,RinehartJJ,SalehM,AllenKO,SellersS,andWaddellMJ.Effectofdocetaxelchemothera-pyontheactivityofagonadotropinreleasinghormonevaccinein patients with advanced prostate cancer. The Prostate, 65:316-21,2005.

Triozzi PL, Allen KO, Carlisle RR, Craig M, LoBuglio AF, andConryRM.PhaseIstudyof the intratumoraladministrationofrecombinantcanarypoxvirusesexpressingB7.1andinterleukin-12 in patients with metastatic melanoma. Clin Cancer Res, 11:4168-75,2005.

AldrichW,RenC,WhiteA,ZhouS-Z,KumarS,JenkinsC,ShawDR,StrongTV,TriozziPL,andPonnazhaganS.Enhancedtrans-duction of mouse bone marrow-derived dendritic cells by re-petitive infection with self-complementary adeno-associatedvirus6combinedwithimmunostimulatoryligands.Gene Ther, 13:29-39,2006

Publications:

Progress


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Improvementinplateletcountinapatientwith

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Hematologicrecovery(improvementofabsolute

neutrophilcount)inapatientwithsevere

neutropeniaduetolargegranularlymphocyte

leukemia.

Inthispatientpresumedtohavemyelodys-

plasticsyndrome,largegranularlymphocyte

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In this patient presumed to have MDS, large granular lyphocyte leukemia was diagnosed, in the laboratory andsuccessfully treated with cytoxan.

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TRANSFUSIONS

In this patient presumed to have MDS, large granular lyphocyte leukemia was diagnosed, in the laboratory andsuccessfully treated with cytoxan.

Pioneering


Researchersinthislaboratoryconducttranslationalinvestigationsofthepathophysiologyofbonemarrowfailure

syndromes,includingaplasticanemia,paroxysmalnocturnalhemoglobinuria,myelodysplasticsyndromesand

relateddiseases.Bonemarrowfailuresyndromes,asstemcelldisorders,areinstructivewithregardtothefunc-

tionofthestemcellcompartment,factorsthatregulatebloodcellproductionandcausesofmalignantclonal

diseasesofthehematopoieticsystem.Twopathophysiologicaspectsarethefocusofourresearch:defective

hematopoieticstemcellfunctionanditsconsequencesandimmunepathogenesisofstemcelldamage.

Inaplasticanemia,stemcelldestructionismediatedbycytotoxicTcells.Weareemployingmolecularmethods

ofTcellreceptor(TCR)analysistoidentifyandcharacterizeautoimmuneTcellclones.TheirTCRclonotypes

havediagnosticutility,andresearchersaredevelopingtestsforautoimmuneconditionsbasedonthemeasure-

ment of the frequency of the pathogenic clones in blood and tissues affected by the disease. Identification of

expandedTcellsclonesbasedontheiruniqueTCRstructurecanalsobeappliedtostudyanti-tumorimmune

surveillancesuchasthatseenfollowingallogeneicbonemarrowtransplantationintheformofthegraftversus

leukemiaeffect.Usingthistechnology,variousstudiesareconductedinclonalTcellmalignanciessuchaslarge

granularlymphocyteleukemia,hairycellleukemiaandTcelllymphomas.

Defectivestemcellfunctionmayresultnotonlyinaplasticanemiabutalsoinotherhematologicconditions.

Myelodysplasticsyndromeoftenevolvesfromaplasticanemia.Geneticdamageisakeyaspectinthepatho-

genesisofmyelodysplasiathatoftenprogressesintoleukemia.Duetothehighincidenceofthisconditionin

theelderly,ourstudiesalsodealwiththefunctionofstemcellcompartmentinage.Stemcellsenescence

andexhaustioninageorduringdiseaseareimportanttargetsofthislaboratory’sinvestigations,conducted

usinghigh-densityexpressionandSNP-arrays.

Experimental Hematology and Hematopoiesis

Principal Investigator: Jaroslaw P. Maciejewski, M.D., Ph.D.

WlodarskiMW,GondekLP,NearmanZP,PlasilovaKalaycioM,MaciejewskiJP.Molecularstrategiesfordetectionandquantita-tionofclonalcytotoxicTcellresponsesinaplasticanemiaandmyelodysplasticsyndrome.Blood.2006EpubApr.13,2006.

SchadeAE,PowersJJ,WlodarskiMW,MaciejewskiJP.Phosphatidylinositol-3-phosphatekinasepathwayactivationprotectsleukemiclargegranularlymphocytesfromundergoinghomeostaticapoptosis.Blood.2006;107(12):4834-4840.

WlodarskiM,O’KeefeCL,HoweE,RodriguezA,WarshawskyI,LoughranT,MaciejewskiJP.PathologicclonalcytotoxicTcellresponses-nonrandomnatureoftheTcellrecep-torrestrictioninlargegranularlymphocyteleukemia.Blood.2005;106(8):2769-2780.

RisitanoAM,MaciejewskiJP,GreenS,PlasilovaM,ZengW,YoungNS.Invivodominantimmuneresponsesinaplasticanemiapatients:moleculartrackingofputativelypathogenicTcellclonesby TCRß-CDR3 sequencing. Lancet. 2004;364:355-364.

SzpurkaH,TiuR,MurugesanG,DolaS,HsiED,TheilKS,SekeresMA,MaciejewskiJP.Refractoryanemiawithringedsideroblastsassociatedwithmarkedthrombocytosis(RARS-T),anothermyeloproliferativeconditioncharacterizedbyJAK2V617Fmutation.Blood.EpubJune1,2006.

O’KeefeCL,PlasilovaM,RisitanoAM,RodriguezAR,WlodarskiM,YoungNS,MaciejewskiJP.MolecularanalysisofTcellreceptorclonotypesinLGL-aclonalmodelforpolyclonalresponses.JImmunol.2004;172:1960-1969.

ZengW,ChenG,ZengW,BillingsE,YoungNS,MaciejewskiJP.GeneexpressioninducedinCD34cellsbyInterferon-g,identification of cytokine-specific profiles in immune-mediated bonemarrowfailure.Blood.2006;107(1):167-175.

SloandEM,ScheinbergP,MaciejewskiJP,YoungN.Successfultreatmentofpureredaplasiawithanti-IL-2receptorantibody(daclizumab).AnnInternMed.2006;144:181-185.

Publications:


Invention


This laboratory is focused on finding a key in biochemical change in phosphorylation of topoisomerase II,

aDNAreplicationenzyme,fortherapeuticactivitiesofthechemotherapies,doxorubicinoretoposide.Aclassic

example of translating research findings into clinical care, this discovery may lead to development of an

antibodythatmightbepredictiveoftherapeuticresponsetotopoisomeraseIIinhibitors.

IntheareaofClinicalPharmacology-ExperimentalTherapeutics,researchcurrentlyisbeingconductedin

theregulationoftopoisomerasesduringcellgrowthanddifferentiation,thegoalofwhichistodetermine

the regulatory function of topoisomerase II∂ and ß as downstream effectors of all trans retinoic acid in cell

growthanddifferentiation.Intheareaofmolecularpharmacologyoftopoisomeraseinhibitors,researchers

are testing the functional role of site-specific phosphorylation of topoisomerase II isozymes in cell prolifera-

tionanddrugstabilizedDNAcleavablecomplexformation.Finally,novelagentsforthetreatmentofcancer

arebeingevaluatedduringPhaseIandPhaseIItrialsinpatients.Promisingpre-clinicalleadsareactively

being pursued in translational studies to maximize efficacy and reduce toxicity of cancer chemotherapy.

Clinical Pharmacology- Experimental Therapeutics

Principal Investigator: Ram Ganapathi, Ph.D.

AoyamaM.,GrabowskiDR,IsaacsRJ,KrivacicKA,RybickiLA,BukowskiRM,GanapathiMK,HicksonID,GanapathiR.Alteredexpressionandactivityoftopoisomerasesduringalltransretin-oic acid induced differentiation of HL-60 cells. Blood.1998;92:2863-2870.

TabataM,TabataR,GrabowskiDR,BukowskiRM,GanapathiMK,GanapathiR.RolesofNF-kBand26Sproteasomeinapop-totic cell death induced by topoisomerase I and II poisons inhuman non-small cell lung carcinoma. J Biol Chem.2001;276:8029-8036.

Chikamori K, Grabowski DR, Kinter M, Willard BB, Yadav S,AebersoldRH,BukowskiRM,HicksonID,AndersenAH,Ganap-athiR,GanapathiMK.PhosphorylationofSerine1106 in theCatalytic Domain of Topoisomerase II∂ Regulates Enzymatic Ac-tivity and Drug Sensitivity. J Biol Chem. 2003;278:12696-12702.

Publications:


Taussig Cancer Center: One of the Nations Best

TheClevelandClinicTaussigCancerCenterisrecognizedbyU.S.News & World Report asoneof

thetop15cancercentersinthecountryandtheNo.1cancercenterinOhioinitsannualhospital

survey.The2006surveyalsorankedClevelandClinicthe3rdbesthospitalinthecountry.

Fordetails,visitclevelandclinic.org.

The Cleveland Clinic Taussig Cancer Center, whichwasdedicatedinJuly2000,isoneofthe

world’snewestandmostadvancedcenterforcancertreatment,researchandeducation.Designed

byworld-renownedarchitectCesarPelli,the$50millionfacilityoccupies165,000squarefeet

on Cleveland Clinic’s main campus. Two hundred fifty physicians at Cleveland Clinic in a variety

ofspecialtiesareinvolvedinthetreatmentofcancer,andscoresofbasicandclinicalresearch

projectsareunderwayhereatanygiventime.

The Cleveland Clinic Lerner Research Institutehousesstate-of-the-artresourcesforscientists

astheyinvestigatethecausesofdiseaseanddevelopnewtreatmentstoprolongandimprove

thelivesofpatients.Theinstituteoverseesmorethan1,000researchprojectswithabudgetof

over $124 million. Four-fifths of this budget are received from external grants and contracts —

adramaticendorsementforthequalityofClevelandClinicresearch.Residentsandfellows

arefrequentlyinvolvedintheseprojects.


sixresearchlaboratories focusingondrug

discovery anddevelopment, clinical phar-

macology and experimental therapeutics,

andexperimentalhematologyandhemat-

opoiesis.

From inception, the strategic approach of research programs within

the Taussig Cancer Center laboratories have focused on translation

of research findings from bench to clinic and the pursuit of clinical

observations at the bench. This research on new drugs and diagnostics

targeted at defined molecular structures will continue to increase both

quality of life and length of life of patients at Cleveland Clinic

and worldwide.

For more information on collaboration, training opportunities or clinical

trials, please call Dr. Ernest Borden at 216.444.8183 or 800.553.5056,

ext. 48183, or any of the other investigators through these numbers.

Our vision is to create a premier translational molecular research unit that

will enhance the scientific and academic stature of the Taussig Cancer

Center, produce a new generation of physician scientists, and augment

availability of new diagnostic and therapeutic modalities for our patients.

For more information, visit the Taussig Cancer Center Web site at

clevelandclinic.org/cancer.

05-CNR-015

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