Ovarian cancer carries an extremely poor prognosis when diagnosed at Stage 3 and 4. In most cases, surgical resection followed by chemotherapy leads to an initially promising outcome, which is later reversed when resistant disease emerges. The work of co-investigators Robert C. Bast and Zhen Lu has shown that autophagy is turned on in small, residual ovarian cancer nodules that remain after surgery and chemotherapy. Autophagy is a process in which cellular components (e.g. organelles) are engulfed by vesicles called autophagosomes where they are degraded to provide metabolic fuel to keep tumor cells alive. Although autophagy is known to play a significant role in tumor dormancy and resistanc...

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Ovarian cancer carries an extremely poor prognosis when diagnosed at Stage 3 and 4. In most cases, surgical resection followed by chemotherapy leads to an initially promising outcome, which is later reversed when resistant disease emerges. The work of co-investigators Robert C. Bast and Zhen Lu has shown that autophagy is turned on in small, residual ovarian cancer nodules that remain after surgery and chemotherapy. Autophagy is a process in which cellular components (e.g. organelles) are engulfed by vesicles called autophagosomes where they are degraded to provide metabolic fuel to keep tumor cells alive. Although autophagy is known to play a significant role in tumor dormancy and resistance to chemotherapy, there are no known drugs that can selectively inhibit this process without also affecting normal cells and tissues. In this proposal, we seek to develop peptides that selectively inhibit autophagy by blocking the initiation and maturation of autophagosomes. We are employing a new design technology developed by PI Steven Millward where large peptides libraries (up to 1 quadrillion different compounds) are sieved for binding to two key autophagy proteins - LC3 and Beclin1. Based on the structure of these proteins, we hypothesize that our peptides will prevent binding of other proteins to LC3 and Beclin1 which will prevent autophagy from occurring in cancer cells. The most potent compounds will be tested in mouse models of chemotherapy resistance and tumor dormancy to determine if disrupting the autophagic machinery in tumors results in a slower tumor growth rate. By the end of the project period, we hope to have identified at least two compounds that can be further developed into drugs to break ovarian tumor dormancy and chemotherapy resistance. We believe that this will fundamentally change the way ovarian cancer is managed after chemotherapy and dramatically extend progression-free survival.

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