# Research Project 2: Combined inhibition of AR and PI3K signaling in metastatic prostate cancer: Exploiting reciprocal feedback

> **NIH NIH P50** · SLOAN-KETTERING INST CAN RESEARCH · 2020 · $170,181

## Abstract

The androgen receptor (AR) signaling pathway is the key driver of human prostate cancer. Prostate
cancers are almost always sensitive to blockade of the androgen receptor, and tumors with acquired
resistance to these therapies are often sensitive to second-generation inhibitors of the pathway.
However, the vast majority of men with progressive prostate cancer will ultimately succumb to the
disease. Activation of the PI3K signaling pathway is the second most prevalent oncogenic event in
prostate cancer, occurring in the majority of advanced castration-resistant tumors. The PTEN tumor
suppressor gene is lost or inactivated in 40% of these tumors, and genetic events that activate PI3K are
also found in a significant number of patients. While PTEN loss is the most commonly altered regulator
of PI3K signaling in prostate cancer, recent genomic profiling studies of metastatic castration-resistant
prostate cancer (CRPC) have reported activating alterations in the subunits of the PI3K complex
(PIK3CA, PIK3CB, PIK3R1) in approximately 10% to 20% of cases. Our previous work revealed that
activation of AR-signaling or PI3K signaling each cause feedback inhibition of the other in a reciprocal
fashion. As predicted from this finding, inhibition of androgen receptor signaling activates PI3K
signaling in these tumors and correspondingly, inhibitors of PI3K signaling activate AR signaling. It is
likely that relief of feedback inhibition of the other pathway reduces the benefit of therapy with single
agent AR or PI3K inhibitors. In support of this hypothesis, we showed that combined inhibition of both
pathways has profound therapeutic effects in preclinical models of advanced prostate cancer. The
major goal of this proposal is to optimize such therapies, tailoring the therapeutic strategy to specific
tumor genotypes. We will do this by determining the biologic consequences of different mechanisms of
PI3K activation in prostate cancer, determining the best means of pharmacologically inhibiting PI3K and
AR signaling in prostate tumors with PTEN loss and/or PI3K activation, and optimizing the dose and
schedule of these combinations in novel organoid and genetically engineered mouse models of
prostate cancer. The aims of this proposal are to explore the biologic consequences of PI3K pathway
activation in AR-driven prostate cancer and to determine the optimal combination regimens with which
to treat these tumors.

## Key facts

- **NIH application ID:** 9998860
- **Project number:** 5P50CA092629-20
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** NEAL ROSEN
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $170,181
- **Award type:** 5
- **Project period:** 2001-09-14 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9998860

## Citation

> US National Institutes of Health, RePORTER application 9998860, Research Project 2: Combined inhibition of AR and PI3K signaling in metastatic prostate cancer: Exploiting reciprocal feedback (5P50CA092629-20). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9998860. Licensed CC0.

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