Abstract 5416: Isolation of the PAX8 transcriptional complex to identify novel therapeutic vulnerabilities for ovarian cancer

Abstract

Abstract A central problem in the treatment of ovarian cancer remains the heterogeneity among ovarian tumors. DNA and RNA sequencing studies have demonstrated both intertumoral and intratumoral genetic variation. Despite efforts to elucidate common signaling pathways among various ovarian cancer subtypes, few have led to meaningful patient stratification or to truly individualized targeted molecular therapies. Our proposed set of experiments is a radical departure from the conventional approach to treating ovarian cancer. PAX8, a transcription factor that identifies nearly all high-grade serous ovarian cancers (HGSOCs), is also the master regulator of fallopian tube development. Building off observations pointing to the fallopian tube epithelium as a major site of origin for HGSOCs, we propose targeting the fallopian tube developmental program as the basis for new therapies. This possibility is supported by the observation that knockdown of PAX8 leads to apoptosis in ovarian cancer cells. We hypothesize that blocking the ability of PAX8 to influence its gene targets, either by interrupting PAX8 protein-protein interactions or by inhibiting the products of PAX8-driven signaling, has the potential to eliminate the primary growth stimulus for high-grade serous tumors. In order to achieve that goal, we have identified candidate PAX8-interacting partners using gel filtration chromatography and tandem-affinity immunopurification coupled with mass spectrometry analyses. Interactions have been validated by Western blot, immunofluorescence, and proximity ligation assay. We used ovarian cancer (KURAMOCHI, OVSAHO and OVCAR4) and fallopian tube (FT189, FT194 and FT246) cell lines to determine whether PAX8 protein partners changed between benign and malignant cells. Our preliminary results suggest that PAX8 interacts with other transcription factors such as TEAD4 and components of chromatin-remodeling complexes (RUVBL1, RUVBL2 and CHD4). Many of these factors are known to mediate the effects of oncogenes such as YAP, β-catenin and c-Myc. Further studies will be done in order to decipher the functional contribution of each candidate PAX8-interacting protein. Our ultimate goal is to determine how PAX8 regulates expression of its target genes and how PAX8-interacting proteins influence that function. Inhibition of certain protein-protein interactions may provide novel avenues to abrogate PAX8 function in ovarian cancer cells. Citation Format: Daniele Chaves-Moreira, Marilyn Mitchell, Simone Sidoli, Benjamin Garcia, Ronny Drapkin. Isolation of the PAX8 transcriptional complex to identify novel therapeutic vulnerabilities for ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5416.