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A Novel Therapeutic Strategy for Ovarian Cancer

卵巢癌的新治疗策略

基本信息

批准号：
10588222
负责人：
Paul Hergenrother
金额：
$ 58.72万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-08 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10588222
关键词：
Antineoplastic Agents Aromatase Inhibitors Binding Biological Breast Cancer Model Breast Cancer therapy Cancer Etiology Cancer Model Cancer Patient Cell Death Cells Cessation of life Chemicals Clinical Trials Data Development Discipline Disease Drug resistance Estrogen Receptor alpha Evaluation Excision Funding Gleevec Goals Human Lead Malignant Neoplasms Malignant neoplasm of ovary Modernization Mus Operative Surgical Procedures Outcome Peritoneal Pharmaceutical Preparations Platinum Poly(ADP-ribose) Polymerase Inhibitor Proteins Proteomics Recurrence Selective Estrogen Receptor Modulators Series Serous Shapes Structure-Activity Relationship Therapeutic Index Time Toxic effect Translations Trastuzumab Tumor Debulking Variant Woman Work Xenograft Model anti-cancer cancer cell cellular targeting chemotherapy clinical candidate design effective therapy experience hormone therapy in vivo malignant breast neoplasm melanoma meter mouse model novel novel therapeutic intervention novel therapeutics overexpression patient derived xenograft model patient population patient subsets response success targeted agent targeted treatment tool trait translation to humans tumor

项目摘要

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.

摘要