# Correlative efficacy, biomarker, and mechanistic studies associated with a phase Ib/II clinical trial of treating mCRPC patients with enzalutamide and Venetoclax

> **NIH NIH R21** · ROSWELL PARK CANCER INSTITUTE CORP · 2020 · $204,181

## Abstract

Prostate cancer (PCa) is a heterogeneous malignancy harboring many phenotypically and functionally
distinct cancer cells. Androgen receptor (AR) plays an important role in PCa development and progression.
Androgen-deprivation therapy (ADT) has been used as the first-line treatment in advanced PCa, but patients
generally develop castration resistance within 1-2 years. Castration-resistant PCa (CRPC) is then treated with
antiandrogens such as enzalutamide (Enza); however, patients also quickly develop Enza resistance in several
months. Both ADT and Enza target AR signaling, whose long-term efficacy depends on PCa cells to express
AR. Yet, our work, together with many others', has revealed that untreated PCa harbor not only AR+ but also
AR-/lo PCa cells and this AR heterogeneity becomes accentuated in CRPC. Our recent work has directly linked
AR heterogeneity to distinct ADT/Enza responses, and further demonstrated that both AR+ and AR-/lo
subpopulations of PCa cells may co-evolve under the pressure of ADT/Enza to mediate castration resistance.
 Critically, most current anti-PCa therapeutic efforts have been directed towards targeting AR+/hi PCa cells,
while largely ignoring the AR-/lo cell population. Since AR-/lo cells can also propagate CRPC, simultaneously
targeting the AR-/lo population may inhibit and even prevent resistance to Enza and abiraterone acetate. Our
pre-clinical modeling using matched androgen-dependent and androgen-independent xenograft models of PCa
has identified BCL-2 as a critical driver and also a viable therapeutic target of CRPC. Based on this new
knowledge and promising pre-clinical therapeutic studies, we hypothesize that co-targeting AR+/hi (bulk tumor
cells) and AR-/lo PCa cells in heterogeneous patient tumors using Enza and the BCL-2 inhibitor venetoclax will
achieve superior clinical outcomes. This hypothesis is currently being tested in a new phase Ib/II clinical trial
developed by our research group at RPCCC in collaboration with AbbVie (NCT03751436). In support of the
objectives for this clinical trial, we propose the following correlative studies in this R21 project, with 3 Aims:
Aim 1: To identify patient responders and non-responders to combination Enza/venetoclax therapy;
Aim 2: To identify the best treatment related biomarkers associated with patient response to Enza/venetoclax
 combination therapy; and
Aim 3: To establish clinically relevant 3D organoid models to better understand patient responsiveness and
 tumor heterogeneity.
SIGNIFICANCE/IMPACT: We have assembled an outstanding team of basic and physician scientists for the
proposed correlative studies. Successful completion of this project will facilitate the development of paradigm-
sifting and potentially practice-changing treatment regimens for (Enza-naïve) mCRPC patients. Furthermore,
the proposed studies will have significant impact on the application of circulating tumor cells to
pharmacodynamic modeling of tumor response and their use as a source ...

## Key facts

- **NIH application ID:** 9878278
- **Project number:** 1R21CA237939-01A1
- **Recipient organization:** ROSWELL PARK CANCER INSTITUTE CORP
- **Principal Investigator:** Dean G. Tang
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $204,181
- **Award type:** 1
- **Project period:** 2019-12-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9878278

## Citation

> US National Institutes of Health, RePORTER application 9878278, Correlative efficacy, biomarker, and mechanistic studies associated with a phase Ib/II clinical trial of treating mCRPC patients with enzalutamide and Venetoclax (1R21CA237939-01A1). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9878278. Licensed CC0.

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