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 clonal architecture 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.

Public Health Relevance

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. Our group has discovered that dormant cancer cells are undergoing a process of autophagy or 'self-eating' to maintain energy levels in a nutrient poor environment with few blood vessels. Our efforts will improve outcomes for women with ovarian cancer by 1) understanding mechanism(s) by which dormant, drug resistant cells develop autophagy, 2) exploring the role of ARHI (DIRAS3) in inducing and maintaining dormancy by blocking cancer cell division and preventing development of blood vessels, and 3) repurposing drugs that are specifically toxic for dormant cancer cells that undergo autophagy.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Sathyamoorthy, Neeraja
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University of Texas MD Anderson Cancer Center
Internal Medicine/Medicine
United States
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Zhou, Jinhua; Alfraidi, Albandri; Zhang, Shu et al. (2017) A Novel Compound ARN-3236 Inhibits Salt-Inducible Kinase 2 and Sensitizes Ovarian Cancer Cell Lines and Xenografts to Paclitaxel. Clin Cancer Res 23:1945-1954
Ornelas, Argentina; McCullough, Christopher R; Lu, Zhen et al. (2016) Induction of autophagy by ARHI (DIRAS3) alters fundamental metabolic pathways in ovarian cancer models. BMC Cancer 16:824
Yang, Hailing; Das, Partha; Yu, Yinhua et al. (2016) NDN is an imprinted tumor suppressor gene that is downregulated in ovarian cancers through genetic and epigenetic mechanisms. Oncotarget 7:3018-32
Washington, M N; Suh, G; Orozco, A F et al. (2015) ARHI (DIRAS3)-mediated autophagy-associated cell death enhances chemosensitivity to cisplatin in ovarian cancer cell lines and xenografts. Cell Death Dis 6:e1836
Lu, Zhen; Baquero, Maria T; Yang, Hailing et al. (2014) DIRAS3 regulates the autophagosome initiation complex in dormant ovarian cancer cells. Autophagy 10:1071-92
Lu, Z; Yang, H; Sutton, M N et al. (2014) ARHI (DIRAS3) induces autophagy in ovarian cancer cells by downregulating the epidermal growth factor receptor, inhibiting PI3K and Ras/MAP signaling and activating the FOXo3a-mediated induction of Rab7. Cell Death Differ 21:1275-89
Simmons, Archana R; Baggerly, Keith; Bast Jr, Robert C (2013) The emerging role of HE4 in the evaluation of epithelial ovarian and endometrial carcinomas. Oncology (Williston Park) 27:548-56
Lyu, Tianjiao; Jia, Nan; Wang, Jieyu et al. (2013) Expression and epigenetic regulation of angiogenesis-related factors during dormancy and recurrent growth of ovarian carcinoma. Epigenetics 8:1330-46
Lu, Zhen; Bast Jr, Robert C (2013) The tumor suppressor gene ARHI (DIRAS3) inhibits ovarian cancer cell migration through multiple mechanisms. Cell Adh Migr 7:232-6
Badgwell, D B; Lu, Z; Le, K et al. (2012) The tumor-suppressor gene ARHI (DIRAS3) suppresses ovarian cancer cell migration through inhibition of the Stat3 and FAK/Rho signaling pathways. Oncogene 31:68-79

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