A Novel Therapeutic Strategy for Ovarian Cancer

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Abstract High-grade serous ovarian cancer (HGSOC) causes 70-80% of all deaths from ovarian cancer. The overexpression of estrogen receptor α (ERα) has been observed in ~80% of HGSOC tumors, but despite ERα being targeted by endocrine therapies in breast cancer (using aromatase inhibitors and selective estrogen receptor modulators and degraders), dozens of clinical trials with endocrine therapies for ovarian cancer have been disappointing, and no endocrine therapy is approved for treating HGSOC. We have been taking a different approach to ERα-expressing cancers, developing a suite of compounds that selectively kill via a mechanism distinct from endocrine therapies, through hyperactivation of the anticipatory unfolded protein response (a-UPR) in an ERα-dependent fashion. We have had notable success with this strategy for ERα-positive breast cancer; as detailed in the Background, we synthesized the novel compound ErSO, which has remarkable selectivity for killing ERα-positive cancer cells (IC50 values of ~30 nM) compared to ERα-negative cells (IC50 values of ~12 µM), and induces complete regression in multiple mouse models of ERα-positive breast cancer. While ErSO also has activity against ERα-positive ovarian cancer, it is not suitable for advancement in this setting as its reduced potency combined with its toxicity in vivo give it an insufficient Therapeutic Index. We now seek to build off the promising data on ErSO to develop novel therapeutics for ERα-positive ovarian cancer that operate through hyperactivation of the a-UPR. In Aim 1 we will use the structure-activity relationship for ErSO and physiochemical predictors to construct derivatives that will be iteratively evaluated for their potency against HGSOC and their tolerability in mice, based on the premise that compounds with better LipE values will be better tolerated in vivo. Indeed, using this guiding principle and constructing just a handful of derivatives, we have already identified a promising compound (called ErSO-DFP) that retains potency and selectively against ERα+ ovarian cancer cells but is markedly better tolerated in vivo as compared to ErSO, suggesting great potential for our iterative synthesis/evaluation plan. Top compounds will advance to Aim 2 where they will be assessed in challenging mouse models of HGSOC, including orthotopic, drug-resistant models, and patient-derived xenograft (PDX) models. In Aim 3 we will utilize alkynlyated derivatives and proteomics to identify, in ovarian cancer cells, the precise binding partner(s) of these highly promising anticancer agents and potent a-UPR hyperactivators. Our goal is to have identified a compound suitable for translation to human clinical trials between years 3 and 5 of the funding period. This tightly-focused, hypothesis-driven proposal from a team of experts who have previously brought anticancer drugs to human clinical trials and who have decades of experience in all the necessary disciplines could provide an impactful targeted therapy for HGSOC; this would be a major breakthrough for this vastly underserved patient population.