2011 Program Project Development Grant Recipient – Kenneth Nephew

Kenneth Nephew, PhD
Indiana University
A New Approach to Treating Recurrent Ovarian Cancer and Newly Diagnosed Disease

Co-Investigators
Daniela Matei, MD
John Turchi, PhD

Project Summary

Although most ovarian cancer tumors initially respond to chemotherapy, the cancer typically returns because the tumor becomes resistant to the drugs. Unfortunately, few treatments are available for patients with recurrent disease. Dr. Nephew is studying a new type of drug that might make ovarian cancer cells sensitive to chemotherapy in recurrent disease. The drug removes chemicals, called methyl groups, on the DNA of ovarian cancer tumor cells. By eliminating the methyl groups, the drug is believed to stop the cancer cell growth. Dr. Nephew also will try to determine if this drug plus standard chemotherapy prevents recurrence in patients undergoing their first round of treatment. Dr. Nephew has evidence that recurrence occurs because a population of cancer cells, called ovarian cancer stem cells, are resistant to chemotherapy and these rare stem cells keep the tumor growing. Stem cell growth may also be controlled by methyl groups on their DNA. Eliminating the methyl groups with the drug may kill the stem cells and prevent the tumor from recurring. His research is the first to examine whether these drugs that target methyl groups can destroy the stem cells.

Bio

Dr. Kenneth P. Nephew joined Indiana University (IU) in 1996. He is a Professor of Cellular and Integrative Physiology, and of Obstetrics and Gynecology in the School of Medicine. He is also the Assistant Director for Basic Science Research at IU Simon Cancer Center, and Program Leader of the Walther Cancer Institute, which is affiliated with IU. He is the Co-Director of the IU-Ohio State University (OSU) Center for Cancer Systems Biology. He is the Director of Graduate Education for the Medical Sciences at IU and is highly active in training and educating graduate and medical students in ovarian cancer research. He is the Principal Investigator and co-investigator on numerous grants from National Institutes of Health/National Cancer Institute (NIH/NCI), serves on various editorial boards, scientific advisory committees, and review panels for both the NIH and the American Cancer Society (ACS).

Dr. Nephew’s ovarian cancer research focuses on disease recurrence, and its resistance to chemotherapy. Aberrant DNA methylation is a an “epigenetic hallmark” of most cancers, and the association between increased CpG island methylation and epigenetic inactivation of genes with known roles in tumor development and progression has been demonstrated for essentially all human cancers, including ovarian. In addition, genes known to be involved in drug sensitivity can become methylated in ovarian tumors. His work and the work of others suggest that DNA methylation is reversible in ovarian cancer cells. Thus, he is pursuing the clinical development of epigenetic therapies for this disease. In the laboratory, he is combining pharmacological reversal of aberrant methylation with standard chemotherapy. He recently moved this approach into the clinic as a phase I/II trial with the goal to improve the outcome for recurrent ovarian cancer patients. In addition, his laboratory has identified a discrete subpopulation of ovarian cancer stem cells that are specifically responsible for ovarian cancer initiation, maintenance and growth. He has shown that ovarian cancer stem cells are chemotherapy resistant and likely responsible for secondary recurrences. His research to target these causative cells in ovarian tumors may enhance the potential to eradicate ovarian cancer.

Dr. Nephew received his undergraduate and graduate (PhD) degrees in Reproductive Physiology from the OSU. He subsequently obtained postdoctoral training in cancer biology at the University of Kansas School of Medicine and then the University of Cincinnati College of Medicine, where he was supported by ACS and NIH postdoctoral fellowships.