# Novel Therapeutic Strategies to Co-Target Undifferentiated Prostate Cancer (PCa) Stem Cells and Bulk PCa Cells

> **NIH NIH R01** · ROSWELL PARK CANCER INSTITUTE CORP · 2021 · $432,651

## Abstract

Castration-resistant prostate cancer (CRPC) kills ~28,000 American men each year. The standard-of-care
clinical therapies for advanced prostate cancer (PCa) have been androgen deprivation therapy (ADT) and/or
chemotherapies (CT). ADT, aiming to block androgen synthesis (e.g., abiraterone) or to inhibit androgen
receptor (AR) signaling (e.g., enzalutamide), achieves impressive short-term clinical effects by de-bulking
primary tumor and reducing serum PSA. The reported survival benefit, however, is measured ONLY in months
and most `castrated' patients eventually develop CRPC. Similarly, CT drugs including taxanes (docetaxel and
cabazitaxel) and cisplatin have been used to treat advanced and recurrent PCa but resistance rapidly
develops. The cellular origin and molecular mechanisms underpinning the emergence, sustenance, and
progression of CRPC and CT-resistant PCa remain poorly understood. Systematic studies from our lab
over the past 16 years on dissecting PCa cell heterogeneity and plasticity have pinpointed a population of
phenotypically undifferentiated PCa stem cells (PCSCs) that frequently lack AR and are largely dormant,
which, together, render them INHERENTLY resistant to both ADT and CT. Importantly, PCSCs frequently
become the predominant cell population in therapy-resistant tumors and may function as a cell-of-origin as well
as tumor-propagating cells for CRPC. These observations lead to our overarching hypothesis that
combinatorial targeting of bulk PCa cells with ADT or CT, and PCSCs with novel strategies, will inhibit both
cancer cell stemness and cellular plasticity, and achieve superior therapeutic efficacies and prevent/overcome
therapy resistance. We test this hypothesis with 3 Specific Aims.
Aim 1): To test the hypothesis that combining enzalutamide with Venetoclax (a newly and the ONLY FDA-
approved BCL-2 inhibitor) will delay/prevent CRPC. Our recent xenograft modeling coupled with RNA-Seq
 and experimental therapies has pinpointed BCL-2 as a critical PCSC survival factor and a driver of CRPC.
Aim 2): To test the hypothesis that combining enzalutamide with anti-PCSC microRNAs will delay/prevent
CRPC. We have demonstrated that several tumor-suppressive miRNAs, including miR-34a and miR-141 are
 critical negative regulators of PCSCs and potently inhibit PCa metastasis and extend animal survival.
Aim 3): To test the hypothesis that combining CT with anti-PCSC microRNAs or anti-BCL-2 will significantly
extend the therapeutic efficacy of chemotherapies.
These aims will be accomplished by combining extensive xenograft/PDX modeling and therapies with in-depth
mechanistic studies. Accomplishment of the goals should help establish important principles, validate novel
hypotheses, elucidate the molecular underpinnings of PCa subpopulation dynamics in response to treatments,
and identify novel therapeutics and therapeutic regimens against different PCa subpopulations. These should
facilitate rapid translation of our preclinical knowledge t...

## Key facts

- **NIH application ID:** 10164736
- **Project number:** 5R01CA240290-03
- **Recipient organization:** ROSWELL PARK CANCER INSTITUTE CORP
- **Principal Investigator:** Dean G. Tang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $432,651
- **Award type:** 5
- **Project period:** 2019-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10164736

## Citation

> US National Institutes of Health, RePORTER application 10164736, Novel Therapeutic Strategies to Co-Target Undifferentiated Prostate Cancer (PCa) Stem Cells and Bulk PCa Cells (5R01CA240290-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10164736. Licensed CC0.

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