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Funded Investigators & Programs
Doris Germain, Ph.D.
Assistant Professor, Dept of Medicine
Mount Sinai School of Medicine
Breast cancer affects 140,000 women each year. Approximately 49,000 (35%) of these cancers are positive for the presence of the cyclin D1 protein. Last year, we reported that cyclin D1 positive breast cancers are sensitive to a novel drug formally called Velcade now renamed Bortezomib. This year, we made important findings regarding the molecular mechanism underlying the increased sensitivity of these cells to Bortezomib. We found that cyclin D1 blocks the action of STAT3, a protein that normally prevents cell death. We have confirmed the negative correlation between cyclin D1 and STAT3 in a large number of human cancer samples including 96 breast cancers. In addition, we discovered that blocking the pro-survival pathway regulated by STAT3 specifically lower the threshold required for induction of cell death by Bortezomib. The implications of our findings are far reaching since Bortezomib is an increasingly popular drug used in the clinic but its efficacy varies widely from one tumor type to the other. Therefore, the identification of cyclin D1 as a predictive marker for response to Bortezomib-based therapy represents an important step in optimizing the use of this drug in the clinic. This work is currently under review for publication in the renowned Journal of the National Cancer Institute.
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Josep M. Llovet, MD
Professor of Research at the BCLC Group
Hospital Clinic of Barcelona
Barcelona, Spain
Associate Professor of Medicine and Director
of the HCC Research Program
Mount Sinai School of Medicine
New York, New York
Josep M. Llovet, MD, is Professor of Research at the BCLC Group, Liver Unit, IDIBAPS, Hospital Clinic of Barcelona, and Associate Professor of Medicine and Director of the HCC Research Program at the Mount Sinai School of Medicine, New York.
Professor Llovet has written more than 100 manuscripts in the area of clinical and translational research in hepatocellular carcinoma (HCC) that were published in various journals including New England Journal of Medicine, Lancet, Cancer Cell, Journal of National Cancer Institute, Gastroenterology, and Hepatology, with a total Impact Factor of 700 and more than 4.500 personal citations. He is currently Executive Secretary of the International Liver Cancer Association (ILCA), Associate Editor of the Journal of Hepatology and Liver Transplantation, has lectured in more than 200 international meetings, and is the principal investigator of an NIH-NIDDK R01-award, I+D grant and several competitive private grants. The main achievements of Professor Llovet’s career have been to establish a novel staging system for HCC, and to provide evidence of efficacy for two standard therapies: chemoembolization and sorafenib, a novel tyrosine kinase inhibitor.
Professor Llovet has been working in the clinical and translational research area of HCC, the third-leading cause of death worldwide. He is currently leading international randomized trials in HCC and working in developing a molecular classification of the disease, understanding the genetic aberrations and signaling pathways involved in hepatocarcinogenesis and in the identification of new molecular targeted therapies. For that purpose he has organized the HCC Genomic Consortium, which includes 4 centers: IDIBAPS-Hospital Clínic (Barcelona), Mount Sinai (New York), Dana-Farber-MIT-Broad Institute (Boston) and NCI (Milan).
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Eduardo Farias,Ph.D. Assistant Professor of Medicine
Christine Marzan, Postdoctoral Fellow
Rafael Mira-y-Lopez, M.D., Ph.D., Associate Professor
Division of Hematology and Medical Oncology
Mount Sinai School of Medicine
VITAMIN A AND BREAST CANCER
Vitamin A is processed in breast cells to retinoic acid. Retinoic acid binds to specialized receptors that turn on differentiation genes and turn off proliferation genes. We are working with mice in which the receptors that bind retinoic acid have been "erased". We want to find out if these mice develop breast cancer. If they do, this will provide conclusive evidence that retinoic acid receptors are very important in stopping breast cancer from developing. We are also using other mice that develop breast cancer to find out if treating them with retinoic acid-like drugs will prevent the disease. We think it will but not always, we need to understand why that is. Finally, we are studying a protein that binds vitamin A. We have reason to believe that breast cells need this protein to process vitamin A to retinoic acid. We are testing whether we are right using a special breed of mice. These experiments, in which we use mice as a stand-in for humans (they are genetically similar to us!), are long-term experiments, mice have a life span of 2 years and, as in humans, tend to develop breast cancer late in life.
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Liliana Ossowski, Ph.D.
Professor, Medicine/Hematology & Medical Oncology
Professor, Oncological Sciences
Professor, Center for Anatomy & Functional Morphology
Mount Sinai School of Medicine
Our goal is to find ways to force cancer cells that have spread from the primary tumor into distant organs, into state of permanent, or at least protracted, dormancy. This would mean that these cells will not be able to divide to form metastases and thus will pose no danger to the patient.
We found that two proteins, both present on the membrane of cancer cells, interact with each other starting a cascade of events that leads to cancer cell growth. One of this proteins called integrin is expressed on both cancer and normal cells, the second, urokinase receptor, is highly expressed only on cancer cells. The two interact only when both are present at high level.
In 2005 we were able to precisely pinpoint the site on the urokinase receptor to which the integrin binds to initiate the cancer growth promoting cascade. This work has been submitted for publication. We are now using this finding to test a large (100,000) collection of compounds searching for those that will break the bond between the two proteins and force cancer cells into dormancy. We are using two approaches. One is an unbiased screening of all the compounds in the collection, somewhat of a "brute force approach". The second, done in collaboration with a computer biologist in the Department of Structural Biology at Mount Sinai, uses the information we generated to probe for those chemicals that specifically bind to the area off interest. We screened 12,000 compounds and found several hundreds that fulfill this first requirement. These will now be screened in our biological test.
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Elisa Wurmbach, Ph.D
Assistant Professor, Medicine/Hematology & Medical
Oncology Mount Sinai School of Medicine
Josep Llovet, M.D.
Visiting Professor, Dept. of Medicine, Division of Liver
Diseases Mount Sinai School of Medicine
Gene Expression Profiles In Preneoplastic Lesions And Liver Cancer In Hepatitis C Virus (HCV)-Cirrhotic Patients
Liver cancer is the fifth most common neoplasm in the world, and the leading cause of death in cirrhotic patients. Despite several advances, key issues that may improve diagnosis and prognosis remain unresolved. Before cancer is established alterations in gene expression are manifested, but biomarkers, which indicate reliably different stages of the disease, including the progression of liver cancer are not known. The aim of our study is to analyze the gene expression profiles in order to identify biomarkers, which can be used for diagnosis and to reach a better understanding of the biology underlying the disease, which can lead to the detection of therapeutic "targets". In our comprehensive approach, we focused on HCV induced liver cancer, the most common risk factor in North America, Europe and Japan. Analyzing 38,500 genes in over 75 tissue samples from eight different stages revealed a collection of biomarkers, from which 8, independently confirmed, distinguish highly significantly between cirrhosis, dysplasia and the onset of cancer. In addition, many cellular processes including new pathways/functions in the context of the disease were found to be dysregulated.
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