# Targeting AR variants in advanced prostate cancer

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2021 · $358,955

## Abstract

Although enzalutamide and abiraterone are effective initially for the treatment of castration-resistant prostate
cancer (CRPC), resistance to both drugs occurs frequently through the mechanisms which are incompletely
understood. Considerable evidence from both clinical and experimental studies demonstrated that androgen
receptor splice variant AR-V7 plays vital roles in promoting CRPC progression and induction of resistance to
enzalutamide and abiraterone. AR-V7 is not targeted by either enzalutamide or abiraterone and therefore,
there is an urgent need to develop novel treatment strategies that target AR-V7 to overcome resistance.
Currently, no AR-V7 targeting agents have shown clinical efficacy for CRPC despite convincing experimental
and clinical data supporting a clear role for AR-V7 in resistant CRPC. We previously identified that
niclosamide, an anthelmintic agent approved by the FDA for the treatment of tapeworm infections, inhibits
expression of AR variants such as AR-V7 and overcomes resistance to enzalutamide and abiraterone in
preclinical CRPC models. To improve the bioavailability and potency of niclosamide, we synthesized a library
of niclosamide analogs according to predicted bioavailability. We have identified several novel small molecule
inhibitors of AR-V7 (ARVib). We showed that ARVib has better efficacy in inhibition of AR-V7 expression, AR-
V7 mediated transcriptional activity, and anti-CRPC tumor growth than niclosamide. Furthermore, we
demonstrated that ARVib synergizes with enzalutamide/abiraterone. This proposal is aimed to functionally
characterize and validate the most promising AR variant inhibitors (ARVib) and develop next generation
treatment strategies for resistant CRPC by targeting AR-V7 using ARVib. The overall hypothesis is that
inhibition of AR variants by ARVib suppresses CRPC tumor growth and overcomes resistance to improve
enzalutamide/abiraterone therapy. In Aims 1 and 2, we will characterize and optimize the identified selective
inhibitors of AR variants (ARVib), and evaluate the efficacy of these ARVib for their anti-tumor activity and their
ability to sensitize resistant cells to enzalutamide/abiraterone treatment in resistant CRPC and PDX models in
vitro and in vivo. Aim 3 will determine the mechanisms of action (MOA) of the ARVib in anti-tumor activity and
resensitization to enzalutamide/abiraterone.

## Key facts

- **NIH application ID:** 10072040
- **Project number:** 5R01CA225836-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Allen C. Gao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $358,955
- **Award type:** 5
- **Project period:** 2019-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10072040

## Citation

> US National Institutes of Health, RePORTER application 10072040, Targeting AR variants in advanced prostate cancer (5R01CA225836-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10072040. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*