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.