indian association for cancer researchiacr.org.in/docs_pdfs/iacr news letter vol.26 i1 july...

Indian Association for Cancer ResearchNEWSLETTER

Volume 26 - Issue 1 July - 2010

EDITORIAL BOARD

Editor :

Members :

DR. PRABHUDAS PATELHead, Biochemistry Research Division,The Gujarat Cancer & Research Institute,Ahmedabad-380 016E-mail : [email protected]

DR. SHILIN SHUKLA(Ahmedabad)

DR. RAKESH RAWAL(Ahmedabad)

DR. BHUDEV DAS(Noida)

DR. M. RADHAKRISHNA PILLAI(Thiruvananthapuram)

DR. NISHIGANDHA NAIK(Navi Mumbai)

DR. NEETA SINGH(New Delhi)

DR. SUDHIR KRISHNA(Bangalore)

DR. BHARAT AGGARWAL(USA)

DR. NEWELL JOHNSON(Australia)

IACR EXECUTIVE COMMITTEE

2009-12

President

Vice-President

Secretary

Joint-Secretary

Treasurer

Members

Dr. Rita Mulherkar Navi Mumbai

Dr. Nishigandha Naik Mumbai

Dr. Tanuja Teni Navi Mumbai

Dr. Sorab Dalal Navi Mumbai

Dr. Asha Ramchandani Navi Mumbai

Dr. Arun Kumar Bangalore

Dr. Sharmila Bapat Pune

Dr. R. I. Dave Ahmedabad

Dr. Dinesh Gupta New Delhi

Dr. H. N. Jayaram Indianapolis, USA

Dr. Surya B. Prasad Shillong

Dr. Ajit Saxena Jammu-Tawi

CONTENTS :

Short article:

Announcement:

Activities:

My Journey to an Alien LandMrs. Rema Jayakumar

th30 Annual Convention of IACR

1. Award Winning Essay

2. Activities of the Delhi Chapter for the past year

3. Cancer News

4. IACR Audited Statement of Account 2009-10

5. Spotlight on……….

From the Editor's Desk …….

It gives me immense pleasure to bring out another issue of IACR newsletter. Usually one issue of IACR newsletter is dedicated to the IACR annual convention and other academic activities. It includes report on the Annual Convention of IACR as well as award winning abstracts and award winning essays. But, this time due to some technical reasons we would not be able to incorporate detailed report on the IACR conference held at Kochi as well as award winning abstracts in this issue.

A scientific conference is an opportunity for researchers to present, share and discuss their work and findings. Together with scientific journals, conferences are the most important channel for the exchange of information between researchers. Besides providing a forum for discussion and the sharing of ideas to the education and public outreach, conferences also provide a way to bridge the gap between fellow scientists.

IACR Annual convention is one such forum which brings together the brightest minds in the field of cancer research. This conference is the premier gathering of cancer researchers from both India and around the world. The invited speaker faculty of highly respected scientists and clinicians from around the world discuss their data and experience to update the IACR family on the most important issues and dilemmas of the day in oncology. With multiple sessions, short oral communications, poster presentations in Clinical and Basic Research, there is really always something for everyone. And above all, one can never forget our cultural trend of memorable hospitality of the organizers every year. Active participation of IACR members has established commendable academic values of IACR annual conventions. Let us

thcontinue the same and show our strength through active involvement against this deadly disease at the 30 Annual conference of IACR to be held at IICB, Kolkata during February 2011!

Time and again I have been requesting my fellow colleagues to contribute to this newsletter in the form of articles for publication in this newsletter. I really expect my senior colleagues to contribute for the coming issue.

Greetings!

Prabhudas S. PatelEditor, IACR Newsletter

1Indian Association for Cancer Research NEWSLETTER 1




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Award Winning EssayRecent Advances in Gene TherapyRajendra KumarPh.D. Student, Molecular Immunology Lab, Department of Immunopathology,

th4 Floor, Research Block A,Post Graduate Institute Education and Research, [email protected]

The NBC hit series "Heroes" is one of the greatest hit of recent years. “Heroes”, is a story of the adventures of characters that develop "abilities" because of genetic mutations. Each one has a different supremacy that they use for either good or evil. The fact that a mutant is a gene that has changed, and the fact that the changed characteristic may be passed on to successive generations and may be fatal in some cases, has been found petty to fiction fans. In fact, people all the way through history not knowing about genes and mutations, have not cared about the diseases that people are born with because of genetic mutations.

In 1983 Victor McKusick, Professor of Medical Genetics at Johns Hopkins University, estimated that 2000 to 3000 genetic diseases can be outlined to specific genes. Since that time, researchers have determined that about 2,800 of these diseases are caused by defects or mutations in just one of the patient's genes. About 2 percent of infants suffer from genetic diseases. More recently, a movie named PAA being broadcasted in Indian cinema halls. This movie is all about the child suffering from an extremely rare, severe genetic condition Progeria, wherein symptoms resembling aspects of aging are manifested at an early age.Unearthing of new genetic disorders was not only the triumph we got in the field of human genetics. In the last decades of

ththe 20 century, scientists were consumed with the developing science of genetics and with understanding about the inheritance of certain characteristics. Science of molecular biology advanced tremendously and it triggered remarkable expansion of the understanding of how genes gone skewed could cause maladies. Some researchers in the mid-80s began to play with the premise that if a gene causes disease and trouble, then it should be possible to cure the disease by replacing the “wicked” gene with a “noble” gene.

Background:

This new science of replacing wicked gene with noble and/or functional gene termed as Gene Therapy. Gene therapy appeared to make a sense as a coherent and candid way out to the agony of genetic diseases. Gene therapy is a medical procedure that may hold the cure for many diseases and disorders of humankind. It is one of the rapidly growing fields of medicine, and much like a transplant. However, although transplanting organ is complex, transferring genes involves pool of small molecules that cannot be seen with ever the most powerful microscopes. The genes are transferred by using vectors, i.e. artificially constructed DNA molecules that mostly stem from viruses and carry the desired genetic information. It can be carried out in vivo, or ex vivo.

To modern eyes evidenced by the success of gene technology in agriculture such gene therapy sounds direct and simple, but it has not proven to be so. Like a well-created play, the gene therapy epic has a delighted foundation, a shattering washout, and a hopeful reincarnation. Undeniably, more than any other new biological technology, this one is the most fitful. It had delighted foundation with the Ashi DeSilva case but a shattering washout with the Jess Gelsinger case. Even worse, in 2002 a French trial to cure SCIDs, led by Dr. Alain Fischer and initially thought to be the most successful ever, suffered a setback when two of the participants developed a vector-induced leukaemia. Now as it is turn for reincarnation. The woe besetting various trials does not label the culmination of gene therapy saga, but it has helped researchers define the problems that must be undertaken in a way to improve the ratio of risk to benefit of this procedure. Safer vehicles must be found or designed, strategies must be developed to minimize immune rejection of the vector, and greater emphasis must be placed on risk assessment.

Past:

Current and Future:

Gene Therapy for Genetic Disorders:

Carrier in Gene Therapy:

Newer techniques in Gene Therapy:

Many important medical advances have been made by gene therapy in less than two decades. Within such a short time span it has been transformed from conceptual stage to technology development and workroom research to clinical translation trials for a variety of fatal maladies. Among the most notable advancements are in genetic disorders like bubble boy disease (ADA-SCID), Chronic Granulomatous disorder, Haemophilia, Congenital blindness, Lysosomal storage disease, Muscular dystrophy and acquired diseases like Cancer ( Brain, Breast, Skin, Colon, Lung and Kidney), Neurodegenerative disorders (Alzheimer's disease, Huntington's disease and Parkinson's disease), Hepatitis, HIV and Diabetes.

A carrier called a vector is used to deliver the therapeutic gene to the patient's target cells. Most common in use vector is genetically altered virus that carries human DNA. A well-known character of virus is delivering the encapsulated genetic material to human's cells after infections are being used by scientists as a strategy for insertion of therapeutic genes. Different types of viruses used as gene therapy vectors are Retroviruses, Adenoviruses, Adeno-associated viruses, Herpes simplex viruses. Newer approaches include, non-viral artificial spherical carriers made up of lipid with an aqueous core. These are called Liposomes, which carry the therapeutic DNA. Therapeutic DNA can also be transfected by chemically linking the DNA to a molecule that will bind to special surface or intracellular receptor.

thNow scientists are planning to develop and introduce 47 artificial human chromosome into target cell. This chromosome would remain autonomously alongside the standard 46, not affecting their workings or causing any mutations. It would be a large vector capable of carrying substantial amounts of genetic code, and scientists anticipate that, because of its construction and autonomy, the body's immune systems would not attack it. The only problem anticipated with this potential method is the difficulty in delivering such a large molecule to the nucleus of a target cell.

Viral and non-viral vectors have been examined as a delivery medium for good number of gene copies in cells. Sometimes though, adding a "good" copy of the gene won't solve the problem. If the mutated gene encodes a protein that prevents the normal protein from doing its job, adding back the normal gene won't help. Some methods been developed to get rid of

dominant negative gene. These are;1. SMaRT: Spliceosome-Mediated RNA Trans-splicing.

This technique targets and repairs the messenger RNA (mRNA) transcripts copied from the mutated gene.

2. Triple-helix-forming oligonucleotides: Triple-helix-forming oligonucleotide gene therapy targets the DNA sequence of a mutated gene to prevent its transcription. This involves the delivery of short, single-stranded DNA, which binds specifically in the groove between the double strands of the mutated gene's DNA. Binding produces a triple-helix structure that prevents that segment of DNA from being transcribed into mRNA.

3. Antisense: Antisense gene therapy aims to turn off a mutated gene in a cell by targeting the mRNA transcripts copied from the gene.

4. Ribozymes: This gene therapy aims to turn off a mutated gene in a cell by targeting the mRNA transcripts copied from the gene. This approach prevents the production of the mutated protein. Most often, they act as molecular scissors that cut RNA.

In the UCL Institute of ophthalmology at UK, one research group has announced results from the world's first clinical trial to test a revolutionary gene therapy treatment for a type of inherited blindness. The results claim that the experiment was safe and can improve vision. In another study conducted at University of Texas, combination of two tumor suppressing genes delivered using liposomes, drastically reduces the number and size of lung cancer tumors in mice. From another study in cancer, researchers at the National Cancer Institute (NCI), successfully reengineered lymphocytes, to target and attack cancer cells in patients with advanced metastatic melanoma. This is the first time that gene therapy is used to successfully treat cancer in humans. One of research groups from School of Pharmacy London is working on a formulation testing on mice, which deliver genes containing nanoparticles to cancer cells to target unapproachable cancer cells. Furthermore, Gene therapy is effectively used to treat two adult patients for a disease affecting myeloid cells. The study is the first to show that gene therapy can cure diseases of the myeloid system. Moreover, a gene, called Atoh1, which stimulates the growth of hair cells, was delivered to the cochlea by an adenovirus. The genes triggered re-growth of the cochlear hair cells and many of the animals regained up to 80% of their original hearing thresholds. This study, which many pave the way to human trials of the gene, is the first to show that gene therapy can repair deafness in animals.

Current experiment in Gene Therapy:

Indian Association for Cancer Research NEWSLETTER 3


Conclusion:It seems a hopeful re-incarnation of gene therapy saga. In the field of gene therapy, it is clear that many electrifying inventions are evolving. While many of these new gene therapy and biotech products may yet have unknown risks, they also have the potential for tremendous patient benefits. When developing these new products, sponsors of clinical trials must accept the responsibility to ensure that participants are not exposed to known unreasonable risks.



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Activities of the Delhi Chapter for the past year

Ÿ Held seminar on LNA technology in the analysis of small RNAs at AIIMS on 11.8.09 (sponsored by Genetix)

Ÿ Held seminar on Gynaecological malignancies; Cervical and breast cancer on 13th Nov 2009 along with Indian Women Scientists Association, Delhi branch at NPL, Delhi (sponsored by CSIR). Also Dr Neeta Singh gave a talk at this seminar on 'HPV and Cervical cancer".

My Journey to an Alien LandMrs. Rema Jayakumar

Friends,

I'm privileged to be here, a little nervous perhaps…or make

that very nervous! But I feel I am privileged to be here

because I am a cancer survivor – I've been cancer free for the

past 18 months…lead a normal life, have a job and loving my

life at the moment! And this is a great opportunity for me to

stand up and say thank you to the medical community and all

those who are directly or indirectly involved in cancer

treatment for giving me the opportunity to be like this again.

To all of us the word is a much dreaded one…one

which we keep as far from our minds as possible and hope to

never have to face it. I was no different until one rather

ordinary small lump turned my entire world upside down.

The next day saw me rush to the hospital to be told by my

doctor that it could be cancer and we need to investigate at the

earliest and there on started the emotional roller coaster

ride…the questions, the fears, the prayers. A million

questions went through my mind. Would I survive? How

would my family react? Would the tumor be malignant?

Could I have done something to prevent this? But I think for

me that was a brief phase…only because in my doctor, Dr.

Vijay Kumar – I found someone who put me at ease with his

mild manners and light hearted banter…someone who for me

was first a concerned, helpful, caring person and second a

very efficient doctor. But the agony for waiting for the results

continued as Dr. Vijay Kumar had to leave for Delhi to attend

a conference.Aweek later, post biopsy and mammogram, my

worst fears were confirmed – the tumor was malignant and

surgery was the answer. Of course the first few days were

terrible but I think through it all I managed to stay positive. I

realized that I was lucky to have my husband with me through

all this and then consoled myself that it was in the initial stage.

One of my biggest learning's, during a talk with the counselor

at the hospital, was that many women postpone coming for a

checkup once they have found a lump. Whether out of lack of

awareness or fear of social stigma or sometimes even just

carelessness, there are a lot of lives that could be saved had

they just come in to the hospital a few days/weeks/months

earlier and I believe that is something that I think the medical

community as well as people like me who have been through

and come out of cancer can do a lot to change – I think that

hospitals and the doctors can call on us to talk to people and

there is great benefit in hospitals creating a network of people

like us that cancer sufferers can interact with should they need

CANCER

it. But I also think that it is not only the cancer sufferers who

would benefit but just about all men and women who need to

be sure to keep checking themselves and to be made to

believe that life is

and I wonder if may be the medical community

can be more proactive in getting everyone feel free to

approach them…publicity campaigns to raise awareness,

regular check up camp, doctors talking to ALL patients who

come to them for any kind of illness. I know that in some

developed countries women have to compulsorily go for

smear tests and mammograms every few years as a

preventive measure and I wonder if we can create something

like that in our country…may be the ministry of health could

make it mandatory for all women to go for smear test. I think

very few of our women know that they need to do these tests

and the way it could change your life if you are indeed

diagnosed with something.

I was determined to face the situation with courage and

fortitude and I knew I had it in me to get out of this situation.

So I went through my surgery and chemotherapy…what was

very painful was seeing so much discomfort and pain all

around me. I was very thankful I was surrounded by family

and friends always…especially when I was emotionally low.

Although I think my chemotherapy was uneventful mostly,

there were occasions when I wanted to avoid chemotherapy

or wanted to whip the needle out of the back of hand during

the chemo because the whole process was time consuming

and dreaded to think that in case the nurse did not get my

vein…didn't have the courage – for without chemo, what

would life be? Grateful I did not have that many side

effects…I carried on. I have often wondered if some

counselors in the chemo ward would be beneficial. Reading

inspirational books and passages and talking openly to people

helped me to stay positive.

I think one of the reasons I was able to remain positive

throughout is that I was blessed with great doctors – Dr.

Ganesh and Dr. Vijay Kumar. Their approach was to keep me

informed about what was going on at all times, the impact it

would have on me without confusing me and always

lightening up the atmosphere with their jokes and banter. I

also had excellent nurses and a very supportive family and

friends. I found everyone

associated withAmrita Hospital warm, friendly and caring.

I think it is so important for the medical fraternity to involve

the families of patients because they are in reality going

through a lot of what the patient is going through and it's not

easy for them.

just too important to be bothered about

social stigma

To me that was the best medicine.



The most important lesson is that a positive mindset does help

a lot. If not to actually cure, then to atleast make the journey a

little more bearable. Is there a way we can try and help people

build this mindset…is it counseling sessions in the hospitals,

support networks created by the doctors/hospitals, resources

for patients so they can get to know what they are going

through and how to get through – books, videos, any kind of

material that will help them and I think this coming form the

doctors is the most effective.

I really appreciate my life now and don't take it for granted.

As a person, I have changed because I am able to accept

people for what they are and less concerned about what

people think!

I wish the scientists accomplish many important research

goals aimed at developing better cancer treatment and

prevention strategies so that we can wipe out this disease

forever.

I pray for everyone battling cancer – patients, doctors,

scientists and nurses and I thank you for your work in this

field.

Thank you



6



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10

Length of Telomeres Linked to Risk for Some Cancers

findings on

genome

leukocytes

Drug that Inhibits DNA-repair Enzyme Shrinks Some Breast and Ovarian Tumors

olaparib

In one of the first prospective studies of its kind, European researchers have found an association between the length of DNA-protein complexes, known as telomeres that are at the ends of chromosomes and the risk of incident cancer and cancer mortality. Dr. Peter Willeit of the Innsbruck Medical University in Austria and his colleagues published their

July 7 in the Journal of the American Medical Association.

Telomeres are biological markers for aging; each time a cell divides, telomeres lose a small amount of DNA and become shorter. These structures help protect the , and shortened or damaged telomeres may lead to the chromosome instability that is associated with cancer.

To prospectively test for associations between telomere length and cancer incidence or death, the researchers measured telomere length in white blood cells, or , from 787 men and women in the Bruneck Study, a cross-sectional population-based survey of atherosclerosis carried out in the small town of Bruneck, Italy. This baseline testing was done in 1995, when participants were free of cancer. After 10 years of follow-up, 92 of 787 participants (11.7 percent) had developed cancer and 44 had died of the disease.

As had been seen in previous studies, individuals with shorter telomeres at baseline had higher risks of cancer. The risk was highest in the group with shortest telomeres and lowest in the group with longest telomeres. An association was also seen with cancer mortality overall. . The authors noted that the sample size was too small to precisely assess associations between telomere length and specific types of cancer. Future studies would need to include participants of other races and ethnicities, as well as geographic regions. These studies could also test telomere length in a variety of tissues rather than in the easily accessible leukocytes, the authors said.

In two small phase II clinical trials, the drug , which blocks a DNA-repair enzyme called PARP, shrank tumors or stopped the progression of advanced breast and ovarian cancer in some women with inherited BRCA1 or BRCA2 gene mutations. Cancer cells with BRCA mutations are thought to be especially sensitive to PARP inhibition because they have

a defect in another DNA repair pathway and therefore rely on the pathway that involves PARP. The results of both studies were published online on July 6 in The Lancet.In the Dr. Andrew Tutt of King's College London School of Medicine and his colleagues enrolled 54 women with locally advanced or metastatic breast cancer and verified BRCA1 or BRCA2 mutations. All of the women had undergone at least one prior chemotherapy regimen. Half of the women received 400 mg of olaparib twice daily—the maximum tolerated dose—and the other half received 100 mg of olaparib twice daily, which preliminary studies showed is the minimum amount to have antitumor effects.

were presented at the 2009 ASCO annual meeting.

Tumors shrank in 11 of the 27 women in the 400 mg group and 6 of the 27 women in the 100 mg group. The median duration of this response was 144 days in the former group and 141 days in the latter. Twelve women who participated in the study experienced temporary stabilization of their disease.

The women who received 400 mg had a median survival without disease progression of 5.7 months compared with 3.8 months in the 100 mg group. Forty-one percent of patients in the 400 mg group and 33 percent of patients in the 100 mg group experienced a high-grade side effect, including fatigue, nausea, and vomiting.

Similar results were seen in a of olaparib for recurrent ovarian cancer in women with BRCA1 or BRCA2 mutations. In that trial, led by Dr. M. William Audeh of Cedars-Sinai Medical Center in Los Angeles, 33 women received 400 mg of olaparib twice daily and 24 received 100 mg twice daily. Tumors shrank in 11 women in the 400 mg group (with a median response duration of 290 days) and 3 women in the 100 mg group (a median response duration of 269 days).

The authors of the breast cancer paper noted that women in both the breast and ovarian trials had received a median of three previous chemotherapy regimens, meaning their disease was highly resistant to treatment. Future trials should compare the efficacy and toxicity of olaparib with traditional cytotoxic chemotherapy, they said.

breast cancer trial,

Preliminary results

parallel phase II trial

Cancer News: Cancer research highlights(courtesy: NCI Cancer Bulletin- July 13, 2010-Volume 7/Number 14)

Announcement

thIndian Institute of Chemical Biology, Kolkata is hosting the 30 Annual Convention of Indian Association for Cancer Research (IACR) during February 6-9, 2011.

Along with the convention an international symposium in the area of cancer to commemorate the 75th year of IICB (1935-2010) is also being organized.

For further details visit www.iacr.org.in

Spotlight on…Joseph Schlessinger- PezcollerFoundation-AACR International Award for Cancer Research Winner-2010. (This award is presented to a scientist of international renown who has made a major scientific discovery in basic or translational research.)

Dr. Joseph Schlessinger is honored in recognition of his groundbreaking basic discoveries in cancer research. He has worked tirelessly to exploit his research data for clinical use in cancer patients and has succeeded to a significant degree. Many cancer patients across the world are now benefiting directly from the combination of his superb science and his commitment to translating it for the benefit of patients.

Dr. Schlessinger's pioneering studies have paved the way for the discovery of new families of cancer drugs that inhibit receptor tyrosine kinases (RTKs), including Sutent (SU11248/Sunitinib)(FDA approved in 2006), which blocks the action of PDGFR, VEGFR and c-Kit is used for both the treatment of renal cancers and gastrointestinal stromal tumors (GIST). Sutent also appears to be effective in treatment of non-small cell lung cancer patients and a population of breast cancer patients.

Dr. Schlessinger was the first to demonstrate that epidermal growth factor (EGF) binding induces dimerization of the epidermal growth factor receptor (EGFR), and to propose that ligand-induced receptor dimerization is crucial in activation of (and signaling by) the receptor. This work actually predated the findings that EGFR and the insulin receptor are protein tyrosine kinases. His lab also generated the first monoclonal antibodies (mAbs) against EGFR. The Schlessinger laboratory used these antibodies to

purify and clone EGFR, allowing the first biochemical studies with the purified receptor. His laboratory was also the first to show that co-expression of a truncated EGFR interferes with activation of full-length EGFR. This finding had a dramatic impact on the field of growth factor receptor signaling, cancer research, and cell signaling in general.

Dr. Schlessinger's studies have paved the way for the development of Erlotinib (Tarceva) and Gefitinib (Iressa), which are EGFR inhibitors used for treating colon and lung cancers, plus Imatinib (Gleevec), an Abl and c-Kit inhibitor used for treating CML and GIST patients. In a newer phase of superb studies, published in Cell in July 2007, the Schlessinger laboratory used crystallography to show how the Kit RTK (the receptor for stem cell factor) is activated. This is a key cancer target in GIST and other cancers, and these seminal data promise more novel approaches for the development of targeted cancer therapeutics.

Inaugural function of the IACRCON-2010Swami Poornamritananda Puri, General Secretary of the MA Math inaugurated the conference. The gracious presence of Dr. Rita Mulherkar, President, IACR, Dr. Tanuja Teni, Secretary, IACR, Dr. Prem Nair, Medical Director, Amrita Institute of Medical Sciences and Dr.T. S. Ganesan, Chair, Cancer Institute and Institute of Molecular Medicine at Amrita added to the glory of the function.

Over 300 delegates from all over India and abroad actively participated in IACRCON-2010.

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