# Therapeutic agents targeting nuclear receptor signaling in distinct molecular subtypes of breast cancer

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2020 · $585,752

## Abstract

Project Summary/Abstract
Breast cancer (BC) has several distinct molecular subtypes, including estrogen receptor (ESR1) positive and
triple negative BC (TNBC). A significant proportion of ESR1-positive therapy sensitive-BCs (TS-BC) initially
respond to antiestrogens or aromatase inhibitors, but become therapy resistant-BCs (TR-BC) and progress to
incurable metastases. Further, TNBC subtype has a more aggressive clinical course and lack targeted
therapies. Development of effective therapies for women with TR-BC and TNBCs represents the highest unmet
need. Recent studies revealed the potential role of several members of the Nuclear Receptor (NR) superfamily
as molecular drivers in TR-BC and TNBC, including the androgen receptor (AR), glucocorticoid receptor (GR)
and the orphan NR tailless (TLX, NR2E1). The specificity and magnitude of NR signaling is mediated by the
interaction between NR and critical coregulators and depending on the molecular context in which NRs and NR
coregulators are altered, they may contribute to BC progression. The variability of the contribution of specific
NRs and NR coregulators to disease progression in TR-BCs and TNBCs poses a therapeutic challenge but also
an opportunity for agents that can target multiple NRs and NR coregulators. We have developed a first-in-class
polyfunctional small molecules, ERXs that have activity in the TR-BCs and TNBCs. ERXs block NR and
coregulator interactions. Uniquely, our preliminary studies identified three lead compounds with differential
activity to distinct BC molecular subtypes: ERX-11 (activity against TS-BC, TR-BCs), ERX-41 (activity against
TS-BCs, TR-BCs and TNBCs) and ERX-1113 (activity against TNBC only). The objective of this proposal is to
further develop lead ERXs to treat TR-BC and TNBC. Our overarching hypothesis is that targeting the NR-
coregulator interactome will have therapeutic utility in treating TR-BC and TNBC. Our initial preliminary studies
indicated that ERX-11 targets ESR1, while the molecular targets of ERX-41 and ERX-1113 are not yet defined.
In Aim1, we will determine the mechanism of action of ERX derivatives using a novel forward genetics approach
to identify the molecular target(s) of ERX compounds in ESR1+ BC and TNBCs and establish the molecular
interactome using unbiased mass spectroscopy-based approaches and whole genome sequencing approaches.
In Aim2 we will optimize the translatability of ERX derivatives and conduct detailed PK, PD, tolerability and
toxicity studies on lead ERX compounds. In Aim3, we will test of the efficacy of ERX compounds in using patient
derived explant tissues, endocrine resistant models, and by using syngeneic, orthotopic xenografts and in patient
derived xenografts (PDX). This proposal is innovative as ERXs block multiple critical protein-protein
interactions, and uniquely have activity against a large number of TR-BC and TNBC cell lines. Successful
completion of the proposed studies will lead to the development of first-in-...

## Key facts

- **NIH application ID:** 9830597
- **Project number:** 5R01CA223828-03
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** Ganesh V Raj
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $585,752
- **Award type:** 5
- **Project period:** 2017-12-14 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9830597

## Citation

> US National Institutes of Health, RePORTER application 9830597, Therapeutic agents targeting nuclear receptor signaling in distinct molecular subtypes of breast cancer (5R01CA223828-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9830597. Licensed CC0.

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