Abstract POSTER-THER-1405: Targeting proteasome-associated deubiquitinating enzymes for ovarian cancer treatment

Abstract

Abstract Purpose of the study: Recent studies have shown that genetic events in cancer activate signaling pathways that ultimately alter cell metabolism, thereby rendering cancer cells more dependent upon “metabolic pathways” as compared to normal cells. These findings have resulted in refocused efforts in the strategy for the selective design of anticancer therapies to target the metabolic dependencies of cancer cells. Deubiquitinating enzymes (DUBs) are an essential component of the ubiquitin-dependent protein degradation system and, owing to their recently described role during cancer progression and chemoresistance, DUBs are an attractive new target for cancer treatment. The purpose of our study is to develop novel small molecule inhibitors of proteasome-associated DUBs as an alternative therapeutic approach for treatment of resistant forms of ovarian cancer. The rationale driving this study is that up-regulation of DUBs (at protein and enzymatic activity levels) is a feature of cancer and of chemoresistant versus chemosensitive ovarian cancer. Experimental Procedure: We conducted a high-throughput screening for small molecule inhibitors of DUBs, resulting in the identification of a lead compound, RA-9. Potency, selectivity, cell permeability and potential off-target effects of RA-9 were evaluated in vitro in primary ovarian cancer cells derived from clinical specimens and in vivo in a preclinical mouse xenograft model of human ovarian cancer. Preclinical efficacy and drug safety were also evaluated in a mouse model of human ovarian cancer. Summary of the data: RA-9 was shown to be a potent, selective and cell permeable inhibitor of a specific subset of DUBs associated with the 19S subunit of proteasomes. RA-9 selectively killed primary ovarian cancer cells derived from patients resistant to chemotherapy at clinically achievable concentrations. Mechanistically, RA-9 caused the onset of apoptosis in ovarian cancer cells via a mechanism involving exacerbation of endoplasmic-reticulum stress responses. In vivo, RA-9 was well tolerated, significantly decreased tumor burden, and increases overall survival in a preclinical model of human ovarian cancer. Conclusion: Our findings indicate that RA-9 has significant in vitro and in vivo anti-cancer activity at doses well tolerated in a mouse xenograft model. Based on these promising data, our laboratory is committed to the further development of this class of inhibitors. This includes medicinal chemistry study to optimize selectivity and potency of our current lead compound and pharmacology efforts to optimize pharmacokinetic and pharmacological properties of RA-9 and its most promising derivatives. Our immediate goal is to rapidly translate our findings from the benchside by performing a phase 0 clinical trial with our new investigational drugs. Importantly, Phase 0 studies are highly feasible in that they require: GLP grade drugs, single doses of drugs that are about 1% of the amount designed for clinical trials and a relatively low number of subjects. This work was supported by the Department of Defense Ovarian Cancer Research Program (OCRP) OC093424 and Minnesota Ovarian Cancer Alliance to MB. Citation Format: Kathleen Coughlin, Thanasak Sueblinvong, Rachel Isaksson Vogel, Ravi Anchoori, Martina Bazzaro. Targeting proteasome-associated deubiquitinating enzymes for ovarian cancer treatment [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-THER-1405.