Columbia Awarded One of First NCI “Provocative Questions” Grants

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.

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. The grant will support Dr. Bestor’s research for five years. He will receive $332,000 in the first year. Allocations for subsequent years are to be determined.