# Modulating HSP70/STUB1 machinery in therapy-resistant prostate cancer

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2022 · $362,398

## Abstract

PROJECT ABSTRACT
Prostate cancer will claim lives of over 30,000 American men in 2020 alone. The disease evolves from primary
tumors to castrate-resistant prostate cancer (CRPC), which only takes around 2-3 years. CRPC is still driven
by androgens such as testosterone which is why anti-androgen drugs are widely used to treat the disease.
These drugs include enzalutamide (XTANDI®), abiraterone acetate (ZYTIGA®) and apalutamide
(ERLEADA™). Although these drugs are highly effective initially, patients often quickly develop resistant
disease to these drugs. Therefore, there is an urgent need to find strategies that control the emergence of anti-
androgen resistant prostate cancer. Researchers have shown that drug resistant CRPC often occurs due to
expression of a variant form of receptor called androgen receptor variant-7 (AR-V7). This receptor can be
activated independent of androgen. Data from my group shows that protein degrading enzyme (STUB1) and its
chaperone protein (HSP70) are altered in resistant CRPC cells. This HSP70/STUB1 complex is a critical
regulator of protein stability/half-life. We found that HSP70/STUB1 is responsible for AR/AR-V7 proteins
homeostasis (proteostasis) and remaining active for long periods. We have shown that modulating the
HSP70/STUB1 complex with a Food and Drug Administration (FDA) approved drug used for parasite infection
namely, niclosamide, reduces the levels of AR-V7 and importantly resensitizes resistant prostate cancer to
anti-androgen therapy. However, niclosamide has a poor characteristic that is hard to reach satisfied
concentration in blood as a cancer therapeutic. To address this, we modified niclosamide to yield a range of
potent HSP70/STUB1 modulators (HSMs) and one of the small molecule compounds known as HSM-7, which
has a better bio-distribution profile and superior effects on killing drug resistant prostate tumors. The
overarching goal of this application is to develop HSMs and build a strong rationale for translating the drug to
the clinic to treat patients with lethal CRPC disease. In this project, we will study HSM-7 on its regulation of
HSP70/STUB1/AR-V7 ternary complex which will be critical to strategize to overcome anti-androgen resistance.
We will discover the multiplicity targets regulated by HSMs through HSP70/STUB1 machinery and dissect how
ubiquitination alteration by HSMs treatment controls oncogenic protein turnover. Additionally, we will evaluate
the drug properties of HSM-7 and test its efficacy in novel patient tumor derived animal and cell models of
CRPC for future clinical trial initiation. The outcomes of the proposed studies will provide a strong rationale for
translating HSM-7 into the clinical setting and in addressing the major unmet need of overcoming next
generation anti-androgen resistance in CRPC patients. We believe that HSM-7 will ultimately increase the
overall survival and improve the quality of life men diagnosed with CRPC.

## Key facts

- **NIH application ID:** 10442601
- **Project number:** 5R01CA251253-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Chengfei Liu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $362,398
- **Award type:** 5
- **Project period:** 2021-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10442601

## Citation

> US National Institutes of Health, RePORTER application 10442601, Modulating HSP70/STUB1 machinery in therapy-resistant prostate cancer (5R01CA251253-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10442601. Licensed CC0.

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