Ovarian epithelial cancer is a persistent cancer and does not go away with treatment. Recurrent ovarian cancer is cancer that has recurred (come back) after it has been treated. Evidence strongly suggests that a reason patients are not cured by current treatments is because a small “pool of malignant cells” responsible for maintaining the disease has not been eliminated. It is now well accepted that ovarian and other types of tumors contain such a pool of cancer stem cells that are able to survive current treatments and continue to feed tumor growth. Chemotherapy decreases tumor growth but also contributes to enriching the population of ovarian cancer stem cells in the tumors that remained, indicating that ovarian cancer stem cells could be one cause of tumor relapse after therapy. Our findings suggest that by targeting the epigenome, that is the chemical compounds that modify the genome and can direct the activity of the genome over time, we can exploit epigenetic vulnerabilities of ovarian cancer stem cells and achieve long-term remission or by eliminating ovarian cancer stem cells possibly develop a cure. Our efforts will identify how key pathways are epigenetically maintained and regulated in ovarian cancer stem cells and epigenetic vulnerabilities that can be targeted to switch off paths responsible for ovarian cancer stem cell survival after platinum therapy. In summary, although ovarian cancer is a chemo-responsive tumor with very high initial response rates to standard platinum/paclitaxel therapy, most women eventually develop recurrence, which rapidly evolves into chemo-resistant disease. Recurrent ovarian cancer is essentially incurable. Designing strategies to prevent disease relapse carries high impact, and we contend that epigenetic vulnerabilities of the insidious pool of ovarian cancer stem cells can be targeted as an Achilles’ heel to eradicate the disease.
This grant was made possible in part by a generous donation from the Randall and Barbara Smith Foundation.
- Daniela Matei, MD
- Heather O’Hagan, PhD
- Marcus Peter, PhD
Professor of Cellular and Integrative Physiology Professor of Obstetrics and Gynecology Indiana University School of Medicine Assistant Director for Basic Science Research Indiana University Simon Cancer CenterDr. Nephew is a Professor of Cellular and Integrative Physiology and Obstetrics and Gynecology at Indiana University. He leads the Ovarian Cancer Research Group at the IU Simon Cancer Center (IUSCC), serves as the Assistant Director for Basic Science Research Bloomington, and is a Program Leader of the Walther Cancer Institute, which is affiliated with IU. He is a Full Member of the Tumor Microenvironment and Metastasis Program and the Breast Cancer Program at IUSCC. Dr. Nephew is the former 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 2016 Indiana University Graduate School Faculty Mentor Award Winner. Professor Nephew joined Indiana University in 1996. He has dedicated his entire professional career to the study of ovarian cancer. Dr. Nephew’s ovarian cancer research has been continuously funded by National Institutes of Health (NIH)/National Cancer Institute (NCI) since 1996. 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, American Cancer Society (ACS), and Department of Defense Ovarian Cancer Research Program. Dr. Nephew’s ovarian cancer research focuses on disease recurrence, and its resistance to chemotherapy. Dr. Nephew has made important contributions defining the characteristics of ovarian cancer stem cells and proposing new strategies to inhibit them. A new paradigm explaining tumor relapse involves the persistence of cancer stem cells. Dr. Nephew is a leader in the field characterizing these malignant cells in ovarian cancer. His collaborative team defined the first phenotype of ovarian cancer stem cells from patient samples. 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. Toward this goal, his laboratory showed that targeting the epigenome, including aberrant DNA methylation (an “epigenetic hallmark” of most cancers including ovarian cancer) inhibited the outgrowth of ovarian cancer stem cells and delayed tumor recurrence. The project is designed to identify and target “epigenetic vulnerabilities” found in the pool of ovarian cancer stem cells that remains after platinum therapy. We will identify how key pathways are epigenetically maintained and regulated in ovarian cancer stem cells. These “epigenetic vulnerabilities” can then be targeted to switch off paths responsible for ovarian cancer stem cell survival after platinum therapy, eradicate the disease and improve the outcome for recurrent ovarian cancer patients. Dr. Nephew received his undergraduate and graduate (PhD) degrees in Reproductive Physiology from the Ohio State University. 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.