Abstract POSTER-TECH-1106: Rational design of molecularly targeted therapy for GAB2-driven ovarian cancers

Abstract

Abstract Studies of cancer genomes indicate that high-grade serous ovarian cancers, the most aggressive subtype accounting for over 70% of all ovarian cancer deaths, are characterized by widespread genomic regions of copy number alterations. Our previous study that systematically assessed 455 amplified genes using open reading frame-based expression approaches for their abilities to transform immortalized human cells has identified the signaling adaptor GAB2 (GRB2-associated binding protein 2) as a potent tumor-promoting gene (*Dunn,*Cheung et al, PNAS 2014). GAB2 gene is located at the chromosome 11q14.1 region that is amplified in approximately 38% of primary ovarian tumors and the amplification event has been associated with poor prognosis in patients. This study investigates the signaling mechanisms by which GAB2 amplification promotes ovarian tumor growth. This will provide us insights into the design of a rational therapeutic strategy. Experimental procedures: We established immortalized human fallopian tube secretory epithelial (FTSE) cells that stably overexpressed GAB2 or a control vector. Gene expression profiling and cytokine arrays were applied to identify signaling pathways altered by GAB2 overexpression. The biological roles of these signaling molecules were assessed in human ovarian cancer cell lines harboring GAB2 amplification/overexpression using a combination of cell-based and in vivo approaches. Summary of data: Increased TNFa signaling was observed in GAB2-overexpressing FTSE cells compared to cells expressing a control vector. This resulted in IKKb-dependent induction of multiple cytokines/chemokines, including IL8, CXCL1 and CXCL2 and others. Suppression of IL8 or CXCL1/2 individually significantly inhibited anchorage-independent growth of GAB2-overexpressing FTSE cells. Suppression of GAB2 in ovarian cancer cells also led to downregulation of IL8, CXCL1 and CXCL2 mRNAs and significantly impaired ovarian tumor growth. We are currently testing multiple IKKb small molecule inhibitors for the ability to suppress IL8 and CXCL1/2 expression. We also plan to evaluate their efficacies alone or in combination with chemotherapy in inhibiting tumor angiogenesis and tumor growth in GAB2-amplified tumors. Conclusions: Overexpression of GAB2 promotes IKKb-dependent induction of multiple cytokines that may enhance tumor angiogenesis and growth of ovarian cancers. We are currently evaluating several IKKb small molecule inhibitors as potential agents to increase the therapeutic efficacy of conventional chemotherapy for ovarian cancers. Funding support: Pilot Study Award, Marsha Rivkin Center for Ovarian Cancer Research (H.W.C.), The V Foundation for Cancer Research (H.W.C.), Liz Tiberis Early Career Award, Ovarian Cancer Research Fund (H.W.C.), American Cancer Society Institutional Citation Format: Hiu Wing Cheung, Chris Duckworth. Rational design of molecularly targeted therapy for GAB2-driven ovarian cancers [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-TECH-1106.