Abstract A24: Hypoxia signaling pathway plays a role in ovarian cancer chemoresistance.

Epithelial ovarian cancer (EOC) is the leading cause of gynecologic cancer mortality worldwide. These cancers are highly heterogeneous and while chemotherapy is the preferred treatment many patients are intrinsically resistant or quickly develop resistance. Furthermore, all tumors that recur ultimately become resistant. Understanding the molecular alterations of primary tumor cells has become a common method to identify genes critical to the development of a drug-resistance phenotype and progression of cancer and could lead to the development of novel therapeutic strategies for successful treatment of patients. DNA copy number alterations are a common occurrence in all cancers. Specific chromosomal regions and focal points favor either gains or losses in DNA and are important in the regulation of various oncogenes and tumor suppressors. Contributions from The Cancer Genome Atlas as well as recent bioinformatic results have identified key players involved in ovarian cancer deregulation. Specifically, we examined the datasets to identify copy number alterations in genes that segregate with platinum response, and further filtered with expression data to identify genes that were amplified.

Our analysis revealed correlations for expression and CNV for several genes. Of the genes identified in the screen we further characterized one gene involved in hypoxia, HIF1α. Hypoxia is a microenvironmental factor which plays a critical role in the development and progression of cancer, chemoresistance, and poor survival. Epithelial-to-mesenchymal transition (EMT) is the process by which adherent epithelial cells convert to motile mesenchymal cells and is now known to also occur in a variety of diseases including the progression of cancer. EMT may reflect an adaptation of cancer cells to survive cytotoxic drug activity, and may thus be responsible for chemosensitivity. Our results have indicated that the gain of HIF1α decreased the level of apoptosis in response to carboplatin. Furthermore, ovarian cell lines undergoing hypoxia are more invasive, have migratory ability, and display a transformed EMT phenotype. Taken together, we provide the evidence of a role for HIF1α as an important regulator of chemoresistance in ovarian cancer and hypothesize EMT as the underlying mechanisms. These results suggest that the inactivation of HIF-1α signaling by novel strategies may be a potential targeted therapeutic approach for overcoming EMT and chemoresistance induced by hypoxia.

Note: This abstract was not presented at the conference.

Citation Format: Noelle L. Cutter, Tyler Walther, Liam Gallagher, Robert Lucito, Kazimierz Wrzeszczynski. Hypoxia signaling pathway plays a role in ovarian cancer chemoresistance. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A24.