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ARHI (DIRAS3) in Autophagy and Dormancy of Ovarian Cancer

Robert C Bast

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National Institutes of Health (NIH)
The persistence of dormant, drug resistant cancer cells after primary surgery and chemotherapy is a major factor contributing to poor outcomes for patients with ovarian cancer. We have found that dormant, drug resistant cancer cells found in >80% of positive "second look" operations exhibit autophagy and express ARHI. ARHI is an imprinted tumor suppressor gene that is found in normal ovarian epithelium and downregulated in 60% of ovarian cancers. Re-expression of ARHI at physiologic levels inhibits cancer cell growth and motility, while inducing autophagy and tumor dormancy. We have developed the first inducible model for tumor dormancy in human ovarian cancer xenografts by re-expressing ARHI with a tet-inducible promoter in ovarian cancer cells lines. Treatment of dormant xenografts with chloroquine, a functional inhibitor of autophagy, can markedly delay outgrowth of dormant xenografts, consistent with the possibility that autophagy is required to provide energy to cancer cells in a nutrient poor environment. Whether small numbers of ARHI expressing autophagic cells in the primary cancer are selected by initial chemotherapy or whether residual drug resistant cancer cells adapt to nutrient poor conditions by re-expressing ARHI and undergoing autophagy is not known. Careful standardization of care for all ovarian cancer patients within the MDACC "Moon Shots" initiative will permit us to answer this question by performing "second look" laparoscopies in all stage III-IV patients in clinical complete response and analyzing clonalarchitecture in primary and second look specimens with whole exome sequencing. Using archival specimens, we have found that persistent cancer cells found at second look laparoscopy have a lower proliferative index and microvascular density than primary cancers, similar to observations in our dormant xenograft model. Re-expression of ARHI inhibits angiogenesis by decreasing levels of pro-angiogenic factors (VEGF, bFGF, TIMP-1) and increasing levels anti-angiogenic factors (TSP-1) in ovarian cancer cells largely through post-translational regulation. Using siRNA screening we have identified 25 proteins that regulate survival of autophagic cancer cells and could provide targets to eliminate dormant cells. We will pursue 3 aims: 1) to determine the mechanism(s) by which ARHI is expressed and autophagy induced in positive second look specimens; 2) to compare mechanisms by which ARHI inhibits proliferation and blocks angiogenesis in dormant xenografts and in positive second look specimens; and 3) to identify targets that regulate survival in dormant autophagic xenografts.

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