Several different kinds of cancers can arise from the ovary that appear quite different under the microscope, respond to different drugs and have quite different outcomes. “Low grade” serous ovarian cancers (LGSOC) resemble normal cells that cover the surface of the ovary and that line fluid-filled cysts within the ovary, arise in younger women, grow slowly, and take years to be lethal. Despite slower growth, LGSOCs are often resistant to conventional chemotherapy and are still deadly. More effective treatment for LGSOC is an important unmet medical need. KRAS is an “oncogene” that drives growth of 30% of all human cancers and about 40 % of LGSOC. Recently, novel treatment strategies are emerging to treat RAS driven cancers, based on the effect of mutant KRAS on the ability of cancer cells to burn calories. KRAS-dependent cancer cells have high demands for energy and meet these needs by triggering “autophagy” or “self-eating” where cancer cells break down their body parts to create energy to grow new cancer cells. Autophagy enables cancer cells to survive when they are starving due to a poor blood supply and competition with other cancer cells for limited nutrients. Inhibition of autophagy using an autophagy inhibiting chemical such as chloroquine kills pancreatic cancer cells with mutant KRAS, but this has not been previously reported in ovarian cancer. Our lab discovered a gene called DIRAS3, a “tumor suppressor” gene that prevents the development of cancer. Loss of DIRAS3 is found in several types of cancer including ovarian cancer. Our preliminary studies suggest that restoration of DIRAS3 effectively quenches RAS signaling and slows or stops cancer growth. Activation of DIRAS3 induces autophagy in KRAS-mutant LGSOC and makes them much more susceptible to blocking autophagy. Moreover, a fragment of the DIRAS3 protein binds to KRAS, inhibiting cancer cell growth and sensitizing cancer cells to death form autophagy inhibition. Combining this peptide fragment of DIRAS3 with anti-autophagic drugs could improve care of women with low grade serous ovarian cancer. The objectives of our study are: 1) to find mechanisms by which DIRAS3 inhibits KRAS signaling and cancer cell growth, 2) to discover mechanisms of action by which DIRAS3 induces autophagy, and 3) to develop much-needed new treatments for LGSOC using the whole DIRAS3 molecule or a peptide fragment of DIRAS3 combined with an autophagy inhibitor. Developing drugs that target mutant KRAS, selectively and directly, could dramatically improve the treatment of patients with LGSOC. Currently, we are trying to target KRAS directly by binding DIRAS3 and its peptide fragment. Durable disease responses will probably require a combination of drugs. Consequently, the proposed study should improve our understanding of the KRAS-dependent cancers and provide potential therapeutic approaches for much more effective treatment of KRAS-mutant LGSOC patients.
Dr. Gamze Bildik Elcik is a postdoctoral fellow in the Department of Experimental Therapeutics at MD Anderson Cancer Center. She received her Bachelor of Science degree in Molecular Biology and Genetics from Istanbul University, Turkey. She became more interested in women's health and earned her Master of Science degree in Reproductive Biology from Koc University, Turkey. Subsequently, she continued her doctoral training in Cellular and Molecular Medicine and received her Ph.D. from Koc University where she was trained in a translational research laboratory and focused on fertility preservation strategies against ovarian damage induced by chemotherapy and radiation in young female cancer survivors.
In 2019, Dr. Bildik Elcik joined Dr. Robert C. Bast’s laboratory at MD Anderson Cancer Center as a postdoctoral fellow to further expand her studies in the field of ovarian cancer. She was awarded TRIUMPH (Translational Research in Multi-Disciplinary Program) Postdoctoral Fellowship supported by the Cancer Prevention Research Institute of Texas which provides continued training in clinical and/or translational cancer research and builds a foundation to conduct translational research. With the support of the Ovarian Cancer Research Alliance, her ultimate goal is to understand autophagy-mediated drug resistance to seek more effective therapeutic interventions for women undergoing treatment for low-grade serous ovarian cancer, who are often underrepresented in basic and clinical research.