# Targeting the Metabolome in Androgen Receptor-driven Castration-resistant Prostate Cancer

> **NIH VA I01** · VA PUGET SOUND HEALTHCARE SYSTEM · 2021 · —

## Abstract

Alterations in metabolism especially lipogenesis are unique to prostate cancer progression and the changes
from benign to malignant prostate epithelium involves a switch from mitochondrial oxidative metabolism to
generate energy needs for cellular processes to aerobic glycolysis in cancer cells. This process is critical for
cell proliferation and new cell membrane synthesis including the continued proliferation driven by the androgen
receptor in most castration resistant prostate cancers (CRPC). Mechanisms driving these metabolic alterations
are not fully understood but the endogenous increase in endogenous lipogenesis by fatty acid synthase
(FASN), an androgen receptor driven gene, and a decrease in 5’AMP-activated kinase (AMPK) activity are
crucial components of the altered metabolic processes driving CRPC. In our Preliminary Data we demonstrate
that alteration in function of these two genes, inhibition of FASN and activation of AMPK, by two new drugs will
suppress growth of enzalutamide castrate resistant tumors in vitro and in vivo. We have shown that alteration
in metabolism will suppress the growth of tumors driven by AR constitutively active variants that were the basis
of my current VA Merit Review. The hypothesis of this project is that targeting activation of AMPK
suppresses PCa proliferation by regulating lipogenesis with subsequent inhibition of AR expression and
activity. In order to address this hypothesis we will first demonstrate expression of AMPK, AMPK-related
subunits (e.g., phospho serine 486, p-acetyl coenzyme A carboxylase), and FASN in tissue microarrays (TMA)
of primary prostate cancer, metastatic CRPC tumors, and prostate cancer patient-derived (PDX) models, and
determine correlation with AR, AR-V7, and AR-variants. We have previously shown a strong correlation
between FASN expression and AR in CRPC in metastatic prostate cancer. In addition, other studies have
shown activated AMPK levels decrease in progression from primary to metastatic prostate cancer and for
primary PCa, this may be predictive of development of metastatic disease. Therefore, we will examine use the
extensive patient material available in the University of Washington/Fred Hutchison prostate cancer program to
determine clinical expression of these cancer progression factors. Next we will determine the mechanism by
which AMPK is activated by BKI 1553 and affects AR transcriptional output. Our preliminary data indicates that
activation of AMPK by the dephosphorylation of Ser486 suppresses growth of AR-driven CRPC. Further, this
activity is activated by BKI 1553 but only in PCa cells that are AR positive. In this aim we will determine the
MOA of BKI 1553 activation of AMPK, potential target(s) and its subsequent mechanism of suppression of AR
expression and transcriptional activity. Next we will assess if antiproliferative actions of BKI 1553 include
transcriptional and post-transcriptional regulation of enzymes in monounsaturated fatty acids (MUSFAs)
meta...

## Key facts

- **NIH application ID:** 10148548
- **Project number:** 5I01BX003324-06
- **Recipient organization:** VA PUGET SOUND HEALTHCARE SYSTEM
- **Principal Investigator:** Stephen R. Plymate
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2016-01-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10148548

## Citation

> US National Institutes of Health, RePORTER application 10148548, Targeting the Metabolome in Androgen Receptor-driven Castration-resistant Prostate Cancer (5I01BX003324-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10148548. Licensed CC0.

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