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Contact: Elizabeth Streich
estreich@columbia.edu
212-305-3689
Columbia University Medical Center

Columbia awarded 1 of first 'Provocative Questions' grants from NCI

Dr. Timothy Bestor's project could overturn a prevailing theory of carcinogenesis

New York, NY (September 20, 2012) — Columbia University Medical Center (CUMC) is one of 50 institutions selected nationwide from more than 700 applications for a "Provocative Questions" grant from the National Cancer Institute (NCI). In a departure from its traditional grant-making process, NCI solicited research proposals related to 24 questions that could lead to significant advances in cancer research. These grants represent new and different ways to identify and address research needs in cancer.

Timothy H. Bestor, PhD, an epigenetics researcher and professor of genetics and development at CUMC, was selected for his proposal, "Methylation Suicide in Cancer," which could overturn a theory of carcinogenesis that has stood for more than 20 years.

Methylation is a chemical modification of DNA that can turn genes off without altering DNA sequence. Cells use DNA methylation to lock genes in the "off" position.

Since the 1980s, scientists have thought that DNA methylation of tumor suppressor genes is a key event in carcinogenesis, driving cells to become cancer cells. However, when Dr. Bestor and his team tried to find examples of tumor progression driven by methylation (with the eventual goal of being able to turn off this methylation), they were unable to find any, either in their laboratory research on breast cancer tissue or through a literature review. This led them to an alternative hypothesis of "methylation suicide," in which methylation changes are part of the normal pathways that kill incipient cancer cells. Dr. Bestor's NCI grant supports the study of this hypothesis.

"We expect that our research will cause people to question scientific dogma, which is always good," said Dr. Bestor, who is also a member of the Herbert Irving Comprehensive Cancer Center (HICCC) at NewYork-Presbyterian Hospital/CUMC. "Our hypothesis is one of the first alternatives to the methylation carcinogenesis model, which has gone unchallenged and untested for more than 20 years.

"If our methylation suicide in cancer hypothesis is correct, then our team—as well as other research teams around the world—can start looking for drugs to enhance the response, make it go off even more and kill more cancer cells," said Dr. Bestor. "We hope to publish our findings soon."

The question associated with Dr. Bestor's research is whether new methods can be developed to discriminate between "driver" and "passenger" epigenetic events, as scientists are better able to identify epigenetic changes that occur during tumor development. Epigenetic events are mechanisms that change patterns of gene expression without affecting the DNA sequence. These changes can persist through cell division and can be passed from parent to offspring.

In short, Dr. Bestor will aim to address is whether new hypotheses can lead to methods to differentiate between events that initiate carcinogenesis versus those that carry it along.

NCI's Provocative Questions project emerged from discussion among veteran cancer researchers. There were a number of questions—some important but not obvious, some that had been asked but abandoned because researchers lacked ways to address them, some sparked by new discoveries or novel technologies—that they believed could stimulate the NCI's research communities to use laboratory, clinical, and population sciences in especially effective and imaginative ways.

Over a period of 18 months, NCI solicited questions from scientists in various fields and at different stages in their careers, ultimately settling on 24 questions that, if answered, could lead to significant research advances.

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For more information about the NIH Provocative Questions project, visit: http://provocativequestions.nci.nih.gov/. A commentary about the project by Harold Varmus, Nobel laureate and NCI director, and Ed Harlow, senior advisor to the NCI director, was published in Nature (January 2012).

Dr. Bestor's collaborators include Hanina Hibshoosh, MD, professor of clinical pathology at CUMC, where he's also director of molecular pathology at the HICCC; John R. Edwards, PhD, assistant professor at Washington University in St. Louis's School of Medicine (a former postdoctoral fellow in Dr. Bestor's lab); and Anne O'Donnell, MD, PhD, a resident at Boston Children's Hospital (a former student in Dr. Bestor's lab). The grant is NIH Project No. 1R01CA170546-01.

Columbia University Medical Center provides international leadership in basic, pre-clinical and clinical research, in medical and health sciences education, and in patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Established in 1767, Columbia's College of Physicians and Surgeons was the first institution in the country to grant the M.D. degree and is among the most selective medical schools in the country. Columbia University Medical Center is home to the largest medical research enterprise in New York City and State and one of the largest in the United States. For more information, please visit www.cumc.columbia.edu.

The Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center and NewYork-Presbyterian Hospital encompasses pre-clinical and clinical research, treatment, prevention and education efforts in cancer. The Cancer Center was initially funded by the NCI in 1972 and became a National Cancer Institute (NCI)–designated comprehensive cancer center in 1979. The designation recognizes the Center's collaborative environment and expertise in harnessing translational research to bridge scientific discovery to clinical delivery, with the ultimate goal of successfully introducing novel diagnostic, therapeutic and preventive approaches to cancer. For more information, visit www.hiccc.columbia.edu.



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