# Synthetic lethal metabolic drug combinations for castration-resistant prostate cancer

> **NIH NIH K08** · JOHNS HOPKINS UNIVERSITY · 2024 · $219,240

## Abstract

PROJECT SUMMARY
This is a proposal for a five-year career development program to study hormonally-determined metabolic
programs as therapeutic targets for prostate cancer. The candidate is currently an Instructor of Oncology at
Johns Hopkins University School of Medicine. The proposal builds on the candidate’s previous research and
clinical experience and integrates two distinct areas of expertise of her mentors, Dr. Samuel Denmeade and Dr.
Erika Pearce, to understand metabolic vulnerabilities induced by high dose androgen in prostate cancer. In spite
of recent advances in prostate cancer therapy development, this disease continues to kill more than 350,000
men per year worldwide. Standard-of-care therapies inhibit androgen receptor (AR) signaling, which often leads
to adaptive upregulation of AR to drive resistance. We have shown that this upregulation of AR constitutes a
vulnerability to high dose androgen and are developing a novel therapy called Bipolar Androgen Therapy (BAT)
in which high dose androgen is provided intermittently to result in cycling of serum androgens to minimize
adaptations to high or low levels of androgens. To date, our clinical trials indicate that BAT is safe, improves
quality of life, and can induce responses in a subset of patients for whom there are very limited therapeutic
options. We are now seeking to expand the population of patients who benefit from BAT by identifying metabolic
synthetic lethal vulnerabilities induced by exposure to high levels of androgens in the initial phase of BAT. This
proposal focuses on identifying metabolic vulnerabilities because (1) a fundamental effect of androgens across
numerous tissues in the body, including benign and malignant prostate, is alteration of cellular metabolism and
(2) metabolic plasticity is an emerging common pathway of resistance to cancer therapies. Our preliminary data
using global metabolomics and a metabolism-focused CRISPR-based genetic screen indicate that high dose
androgen dramatically reprograms prostate cancer metabolism resulting in vulnerabilities including de novo
polyamine synthesis and nucleotide synthesis. Specific aims proposed will interrogate synthetic lethality of high
dose androgen in combination with inhibition of polyamine synthesis (Aim 1) and with inhibition of nucleotide
synthesis (Aim 2). Aim 3 will assess efficacy of combination therapies across a highly characterized panel of
patient-derived xenograft models of castration-resistant prostate cancer that approximate the diversity of patients
with this disease. The outlined career development and research plan will provide the candidate with unique
cross-disciplinary skills that will enable her transition to independence as a physician scientist and identify
promising combination therapies for treatment of patients with castration-resistant prostate cancer.

## Key facts

- **NIH application ID:** 10846603
- **Project number:** 5K08CA273167-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Laura A. Sena
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $219,240
- **Award type:** 5
- **Project period:** 2023-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10846603

## Citation

> US National Institutes of Health, RePORTER application 10846603, Synthetic lethal metabolic drug combinations for castration-resistant prostate cancer (5K08CA273167-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10846603. Licensed CC0.

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