# A Novel Therapeutic Strategy for Ovarian Cancer

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · 2022 · $597,841

## Abstract

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 ta...

## Key facts

- **NIH application ID:** 10446419
- **Project number:** 1R01CA258746-01A1
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
- **Principal Investigator:** Paul Hergenrother
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $597,841
- **Award type:** 1
- **Project period:** 2022-03-08 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10446419

## Citation

> US National Institutes of Health, RePORTER application 10446419, A Novel Therapeutic Strategy for Ovarian Cancer (1R01CA258746-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10446419. Licensed CC0.

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