Modulating HSP70/STUB1 machinery in therapy-resistant prostate cancer

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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.