# Targeting Castration Resistant Prostate Cancer via Potent Inhibition of Signaling Lipids

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2024 · $460,513

## Abstract

Summary
Metastatic castration resistant prostate cancer is uniformly fatal, representing the second-leading cause of
cancer-related death among men in the United States. Despite therapeutic advances with docetaxel, abiraterone
and enzalutamide, prostate cancer progression to lethal castration-resistant prostate cancer (CRPC) remains a
major clinical problem. Rapidly proliferating cancer cells upregulate de novo lipogenesis and cholesterol
synthesis pathways in order to provide lipids for membrane formation and lipid modification of proteins and to
support energy production. The sterol regulatory element binding proteins (SREBPs) are master regulatory
transcription factors that activate genes encoding enzymes required for synthesis of cholesterol and unsaturated
fatty acids. The SREBPs are frequently overexpressed in prostate cancer and other solid tumors and are
associated with tumor aggressiveness and unfavorable outcomes. Interestingly, emerging studies suggest that
in African American (AA) prostate cancer patients - who already have 1.6 times higher prostate cancer incidence
and 2.6 times higher mortality from prostate cancer than Caucasian males - the androgen receptor and
PI3K/Akt/mTOR signaling pathways are more active than in Caucasian prostate cancer patients, frequently
resulting in even greater increase in lipid metabolism. Androgen receptor and the PI3K/Akt signaling can activate
the transcription factor MNX1, leading to induction of SREBP1, which controls expression of numerous lipogenic
genes including FASN, and alters the metabolic state of the prostate cancer cell. Inactivation of SREBPs
represents a novel mechanism by which metabolically-driven tumors can be targeted. The overarching goal of
this preclinical study is to establish key proof-of-concept efficacy and safety data for the use of SREBP inhibitors
against prostate cancer cells, using extensive in vitro and in vivo models. Our proposed studies are focused on
1) defining the function of SREBPs in prostate cancer and identifying biologically significant lipid products of
SREBP activation, 2) evaluating effects and mechanisms of a small molecule inhibitor of SREBP in vitro, and 3)
assessing the anticancer activity of SREBP inhibitors alone and in combination with existing drugs, using cell
line xenograft and innovative patient-derived xenograft models of prostate cancer.

## Key facts

- **NIH application ID:** 10911825
- **Project number:** 5R01CA251560-03
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Salma Kaochar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $460,513
- **Award type:** 5
- **Project period:** 2022-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10911825

## Citation

> US National Institutes of Health, RePORTER application 10911825, Targeting Castration Resistant Prostate Cancer via Potent Inhibition of Signaling Lipids (5R01CA251560-03). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10911825. Licensed CC0.

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