# Therapeutic targeting of orphan NR in ER-negative breast cancer

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2021 · $451,202

## Abstract

ABSTRACT
Triple-negative breast cancers (TNBC) still lack effective targeted therapy, despite the fact that TNBC often
presents as invasive diseases with poor outcome. Subtypes of TNBC show rare or low pathological complete
response (pCR) rates to neoadjuvant chemotherapies. Despite the newly acquired tumor genomics data,
readily actionable, therapy-effective targets are yet to be revealed or established.
Our recent data mining and other tumor analysis revealed that RORC/RORγ, an orphan member of the
nuclear receptor family of transcription factors, is amplified or overexpressed in over 30% of TNBC and that its
overexpression is significantly associated with poor outcomes. Our functional studies revealed that it is
required for growth and survival of TNBC cells, and that its inhibitors, developed recently by us, are highly
effective in killing TNBC cells selectively and stopping tumor growth and metastasis at relatively low doses,
without overt toxicity. With other preliminary studies, we hypothesize that overexpression and/or
hyperactivation of RORγ drives TNBC progression through a novel cholesteromic feed-forward loop and that
targeting RORγ with a potent tumor-selective, small-molecule inhibitor, either alone or in combination with
chemotherapy, can be a novel and effective therapeutic strategy for TNBC. The hypothesis will be tested in 3
specific aims: Aim 1 will establish that overexpressed RORγ drives tumor growth and therapeutic resistance
through its function in reprogramming lipid/cholesterol metabolism; Aim 2 will establish that induction of an
epigenetic switch underlies the superior anti-TNBC potency of the RORγ inhibitor, and Aim 3 will thoroughly
examine the anti-tumor efficacy of the optimized inhibitor using PDX and other tumor models. Successful
completion of the proposed studies should, for the first time, establish RORγ as a new, major driver of TNBC
and effective therapeutic target.

## Key facts

- **NIH application ID:** 10074544
- **Project number:** 5R01CA224900-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Hongwu Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $451,202
- **Award type:** 5
- **Project period:** 2018-12-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10074544

## Citation

> US National Institutes of Health, RePORTER application 10074544, Therapeutic targeting of orphan NR in ER-negative breast cancer (5R01CA224900-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10074544. Licensed CC0.

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