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Boris Wilson Ph.D. • Research Fellow, Pediatric Oncology Department.
Dana Farber Cancer Institute, Harvard University
Advisor: Dr. Charles M. Roberts
The Swi/Snf Tumor Suppressor in
Stem Cell Self-Renewal and Pluripotency
A Malignant Rhabdoid Tumor is an aggressive, highly lethal cancer that strikes young children. While patients afflicted with many cancers are showing improved survival due to more effective treatment strategies, 90% of individuals affected by this disease die. These tumors arise in the brain, kidney, and other soft tissues but all share the same genetic alteration, inactivation of the SNF5 gene. This gene encodes a core member of a protein complex, the SWI/SNF complex, that helps turn genes on or off by altering the shape of DNA. Accumulating evidence has also suggested that perturbations in SNF5 and SWI/SNF may also have a widespread role in the formation of many common cancers, including lung, breast, and prostate cancer. Extensive efforts are being made to understand how perturbations in SNF5 and the SWI/SNF complex lead to such aggressive, wide-spread tumor formation; nevertheless, the mechanistic basis underlying tumor formation still remains elusive.
Accumulating evidence has suggested that genetic programs in stem cells are misregulated in cancer cells. Recent evidence also suggests that the SWI/SNF complex serves a critical role in regulating the growth and identity of stem cells. Consequently, the extremely rapid formation of cancer that occurs following mutation of the SWI/SNF complex may be due to disruption of the key regulatory pathways that control stem cell growth. Designing new drugs which specifically target this small subset of cells which have acquired stem cell like properties might be an important step leading to the treatment of cancer. Thus, a detailed study of the role of the SWI/SNF complex in embryonic stem cells will likely shed important insights to help us understand better the properties of embryonic stem cells, tumor cells which have acquired stem cell like properties, and how defects in the SWI/SNF complex can lead to cancer development. Thus far, we have shown that SNF5 is required for the survival of embryonic stem cells and might have additional roles in maintaining key properties of stem cells. Importantly, we have found that SNF5 binds directly to genes required for the maintenance of stem cell identity. Thus, we are beginning to uncover essential roles for Snf5 in regulating both the growth and identity of stem cells. Future experiments will be aimed at understanding better the genetic programs regulated by SWI/SNF in embryonic stem cells and how inactivation of SNF5 leads to defects in these programs.
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SPINODYSSEY 2006 fully funded Dr. Victor Grann, Professor and Ph.D. Columbia University(NY) through the American Cancer Society:
Dr. Grann is Clinical Professor of Medicine and Epidemiology and Health Policy & Management, College of Physicians & Surgeons and Mailman School of Public Health, Columbia University. A medical oncologist for more than 30 years, in 1977 he received both his M.P.H. degree in Health Policy and Management (Health Outcomes) at Columbia University and a Clinical Research Training Grant from the American Cancer Society (CRTG-98-260-02). His work has focused on quality of life, studies of preferences of breast cancer patients, cost-effectiveness, and decision analysis of heath outcomes related to genetic mutations in breast/ovarian cancer. He also is interested in disparities of care especially in clinical trials. He works in the Women’s Cancer Chemotherapy Clinic at Columbia, where breast cancer patients are evaluated and treated, and is Principal Investigator of the NSABP Study of tamoxifen and raloxifene (STAR) trial for the Cancer Center. Presently he is Director of the Recruitment Core at the Herbert Irving Comprehensive Cancer Center.
Title: “Decision Analysis of Population Screening for BRAC1 and BRAC2 Genes” 3 years, $209,000 which we (SPINODYSSEY) will fully fund.
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SPINODYSSEY 2006 Researcher Victor Grann
gives us an update on his progress.
Dear SPINODYSSEY,
We have recently completed a paper entitled cost-effectiveness of population screening for single mutations of BRCA1/2. The objective of our study was to determine if screening a normal population of women who might have an elevated risk of having a genetic mutation makes sense. We performed a series of cost-effectiveness analyses and found that if one only looks at survival, testing among a population of women such as those of Ashkenazi Jewish descent for genetic mutations is cost-effective. However, when one takes into account quality of life, we found that testing is beneficial only if the strategies to prevent breast and ovarian cancer are acceptable. The message from this study is that we need to develop better preventive treatments, such as tamoxifen or raloxifene to prevent breast cancers. More clinical research is needed before population screening can be recommended on a large scale unless women have 1st degree relatives who were diagnosed with breast or ovarian cancer at a young age.
This past month we are starting work on a project to assess the value of MRI screening among women who have tested positive for these mutations. It will take close to one year to complete. We have been making good progress and are developing preference ratings among a group of women who have tested positive for mutations and are undergoing yearly MRIs and mammograms in Toronto.
Looking forward to seeing you in March.
Victor
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Researchers SPINODYSSEY has partially funded
through the American Cancer Society:
2005: Kevin Janes, PhD, Department of Cell Biology, Harvard Medical School
My work is focused on understanding how breast cells organize to form the hollow, spherical structures that make up mammary glands. When normal breast cells become cancerous, mammary gland architecture is disrupted. These structural abnormalities are among the earliest events in breast cancer, making them difficult to study in animals. To examine early cancers more easily, we culture human breast cells outside of the body to grow artificial mammary structures that resemble those in humans. My project will use cultured glands to identify genes that are important for creating the hollow mammary architecture. Mutations in these genes could possibly predispose women to develop early breast cancers.
2005: Ryan Jensen, PhD, College of Biological Sciences, University of California, Davis, CA
My research will focus on characterizing the product of the BRCA2 gene. Women harboring mutations in the BRCA2 gene have an incredibly high risk of developing breast and/or ovarian cancer at an early age. Understanding the function of BRCA2 and why mutations in this gene lead to cancer has the potential to uncover new therapeutic strategies for treating the disease. Additionally, information gained from the study of cancer caused by a mutation in a single gene such as BRCA2 may provide insight into the origin and etiology of sporadic breast cancer, one of the leading causes of death of women in the United States today.
The importance of the BRCA2 gene is underscored by the fact that mutations in this single gene invariably lead to breast cancer and/or ovarian cancer in an afflicted individual. BRCA2 is known to belong to a class of proteins known as “DNA repair” proteins. DNA is the genetic material that codes for all the proteins in our body. Proteins in our cells carry out most of the processes necessary for life as we know it. Our DNA is under constant assault from both exogenous sources (such as UV light and radiation) as well as endogenous sources (free radicals generated by the process of oxidative metabolism (i.e. breathing oxygen)). DNA repair proteins, such as BRCA2, play a key role in repairing this DNA damage acting as quality control inspectors constantly surveying our genome for mistakes. If a protein like BRCA2 becomes non-functional, due to a mutation, a process called “genomic instability” can occur whereby mutations start to appear in many genes, leading some cells down a path to becoming tumor cells. My research will entail a comprehensive analysis of the isolated BRCA2 protein at the biochemical level. I will utilize a cutting edge technology developed in our lab called “single molecule analysis” where I will actually be able to visualize single protein molecules of BRCA2 working on a single DNA molecule in real time. A detailed understanding of how BRCA2 works will further our knowledge not only of the origin of breast cancer, but may also lead to the development of new therapeutic strategies targeted at proteins involved at the initial stages of cancer development.
2004: Dr. Dennis Slamon, UCLA's Jonsson Cancer Center
Dr. Dennis Slamon is a well-known and highly respected cancer researcher whose work has resulted in the latest treatment for breast cancer, a new approach that attacks the disease by targeting defective genes.
Dr. Slamon, who directs the Revlon/UCLA Women's Cancer Research Program at UCLA's Jonsson Cancer Center, was the primary force behind the development of Herceptin during 12 years of discovery and development research in his lab and clinic. The U.S. Food & Drug Administration approved the drug in 1998 for use against advanced breast cancer. Dr. Slamon now is investigating whether Herceptin is effective in women with newly diagnosed breast cancer.
Development of Herceptin has been cited as the first triumph in an emerging wave of new, more effective therapies designed to fight cancer at its genetic roots. Dr. Slamon, for the first time, proved the theory that if researchers could figure out what was broken in a cancer cell, they could fix it.
The development of Herceptin marks the high point of Dr. Slamon's life's work to date. His research established the relationship between a gene called HER-2/neu and a particularly aggressive form of breast cancer. That discovery led to Herceptin, which can help up to 30 percent of women (60,000 cases) each year who develop breast cancer.
Dr. Slamon said much of the credit for Herceptin should go to the women who volunteered to take the experimental drug during worldwide clinical trials.
"They are the real heroines of this story," said Dr. Slamon, who continues to research new treatments for breast and ovarian cancers.
In addition to conducting the initial research that led to Herceptin, Dr. Slamon also served as principal investigator for the worldwide phase III clinical trials, the final round of testing prior to FDA approval.
In addition to serving as director of the Revlon/UCLA Women's Cancer Research Program at UCLA's Jonsson Cancer Center, Dr. Slamon is a Professor of Medicine, Chief of the Division of Hematology/Oncology and Executive Vice Chair for Research for UCLA's Department of Medicine. Because of his groundbreaking work, Dr. Slamon is invited to speak at conferences worldwide. His papers have been published in such medical journals as Science, Cancer Research, Oncogene, The New England Journal of Medicine and The Journal of the National Cancer Institute.
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2003: Dr. Graham A. Colditz, M.D., Dr.P.H. of
Brigham and Women's Hospital in Massachusetts
"Through this funding, I will pursue work identifying markers in benign breast biopsy that shed light on risk for subsequent breast cancer. To complement this work, we will also explore the role of adolescent diet in the prevention of breast cancer. This work will be conducted within our ongoing cohorts of women followed through the Brigham and Women's Hospital and Harvard Medical School. To bring results of our work to women more broadly than merely publishing in the medical literature, I will continue to refine statistical models for prediction of breast cancer risk and find ways to incorporate such risk prediction in to tools available on the worldwide web. The funding you are providing will support me to pursue this work to cover laboratory expenses and the effort of part of a postdoctoral fellow working with me across this range of research issues."
2002: Dr. Michael DiGiovanna, Ph.D. MD, Associate Professor,
Medical Co-director of Breast Cancer Research Lab at Yale University School of Medicine
Dr. DiGiovanna's current research is focused on "intelligent" new types of chemotherapies and drugs like Herceptin that target & slow the growth of cancerous cells without affecting surrounding healthy tissues.
His laboratory is studying the potential of combining Herceptin and Tamoxifen, two important non-chemotherapy breast cancer treatments. Tamoxifen blocks the effect of estrogen and Herceptin blocks the effect of HER2. Both estrogen and HER2 stimulate breast cancers to grow. It has also been found that they can act together, so Dr. DiGiovanna hypothesized that blocking both simultaneously would be a good way to treat certain types of breast cancers. Dr. DiGiovanna discovered that the combination of Herceptin and Tamoxifen is synergistic at inhibiting the growth of breast cancer cells in the lab, and in mice with breast cancer the combination also worked much better than either drug alone. Other drugs that work by similar mechanisms are now being tested, and the precise effects that these treatments elicit inside breast cancer cells are being examined in an effort to be able to improve further upon such treatment.
Dr. DiGiovanna's time is spent on 70% on research, 30% working with oncology patients and another smaller % he finds the time (!) to teach at the Yale Medical School. His research runs from 01/01/02- 12/31/05.
2002: Dr. Michelle F. Pflumm, Department of Cell Biology in Harvard Medical School
Her research is the identification of chromosome condensation proteins by chemical genetics and runs 07/01/02 - 06/30/05. Her lab previously identified the anti-mitotic small molecule monastrol (originally discovered by phenotypic screening) as an inhibitor of the mitotic kinesin Eg5. Pharmaceutical companies have subsequently screened for inhibitors of Eg5 and identified compounds that have showed great promise in cancer treatment during preliminary animal studies. These findings suggest that the highly conserved kinesin (motor protein) family may contain several novel targets that can be used to identify specific anti-mitotic cancer therapeutics through high-throughput screening. (This is due to the fact that several kinesins are required specifically for cell division).
2001: Dr. John Wysolmerski of Yale University
Dr. Wysolmerski directed a study to discover why breast cancer patients have a high rate of bone metastases. He has successfully isolated the PTHrP or parathyroid hormone-related protein and is currently studying the consequences of its removal on calcium metabolism during lactation. In explaining the role that parathyroid related protein plays in breast cancer metastases, Dr. Wysolmerski said, "There is a communication that occurs between the tumor cells and the bone receptor cells which causes this protein to eat away at the bone." The research focused on understanding the factors by which the tumor cells call forth this bone so that this "machine" can be targeted and degraded.
2000: Dr. David Wah of MIT
"I am studying proteins that destroy other proteins. These proteins are known as proteases, and they have been implicated in metastasis. Specifically, I am trying to understand how proteases find their protein targets. I have now found that proteases have accessory proteins that not only help the proteases find their targets, but these accessory proteins activate the proteases at the same time. I am now focusing on my efforts on how these accessory proteins function.
2000: Dr. Leon Murphy of Harvard University
His work has uncovered a previously unidentified molecular mechanism that is important in the control of cell growth and transformation. "I am working on a pathway, known as the Ras pathway, which is known to cause cancer, and have learned more about how an important component of the Ras pathway functions and contributes to uncontrolled cell growth."
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RIDERS WITH A CAUSE SINCE 2000
P.O. BOX 457 • WESTPORT • CT • 06880-0457
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