# The role of cholesterol homeostasis in enzalutamide resistance

> **NIH NIH R03** · RESEARCH INST OF FOX CHASE CAN CTR · 2021 · $93,500

## Abstract

PROJECT SUMMARY
Prostate cancer (PC) is the most common malignancy among males worldwide, and is the second leading
cause of cancer death among men in United States. A man's life-time risk of developing PC is one in seven.
Importantly, androgen receptor (AR) signaling is vital not only for the initiation of PC, which is initially
androgen-dependent, but also for castration-resistant disease. Enzalutamide (ENZ) is the first and only FDA-
approved second-generation AR antagonist used for the treatment of both non-metastatic and metastatic
castration-resistant PC (CRPC). However, nearly all PC patients develop resistance to androgen-deprivation
therapy (ADT). It has been well established that the progression of PC to castration-resistant growth and
development of ADT resistance is associated with aberrant activation of Akt/mTOR signaling. Importantly,
PI3K/Akt/mTOR axis acts as a transcriptional integrator of the androgen signaling pathway in PC cells. For
many years, the cholesterol homeostasis in PC has been one of the main focuses of research. The consistent
interest in the relationship between cholesterol and PC was largely driven by cholesterol involvement in de
novo androgen synthesis. Our preliminary studies indicate that major cholesterol fractions (i.e. LDL, HDL, and
VLDL) augment activation of Akt/mTOR signaling in PC cells, which coincides with resistance to ENZ.
Sensitivity to ENZ was successfully reinstated following treatment with Akt/mTOR inhibitors. Based on these
findings, we hypothesize that in addition to serving as a precursor for androgen biosynthesis, lipoprotein-
derived cholesterol may promote castration-resistant growth of PC cells via androgen-independent activation of
Akt/mTOR pathway. To test our hypothesis and to validate the therapeutic value of targeting cholesterol
homeostasis in PC cells in order to increase the antitumor efficacy of ENZ, we propose the following Specific
Aims: (1) To establish the role of cholesterol homeostasis in enzalutamide resistance; (2) To improve the
antitumor efficacy of enzalutamide by targeting cellular cholesterol homeostasis. We anticipate that the
proposed studies will gain insights that suggest new therapeutic options for the treatment of PC.

## Key facts

- **NIH application ID:** 10065498
- **Project number:** 5R03CA235060-02
- **Recipient organization:** RESEARCH INST OF FOX CHASE CAN CTR
- **Principal Investigator:** VLADIMIR M KOLENKO
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $93,500
- **Award type:** 5
- **Project period:** 2019-12-05 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10065498

## Citation

> US National Institutes of Health, RePORTER application 10065498, The role of cholesterol homeostasis in enzalutamide resistance (5R03CA235060-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10065498. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*