# A study of IDH1-mutant prostate cancer to identify novel therapeutic targets

> **NIH NIH R21** · JOHNS HOPKINS UNIVERSITY · 2024 · $421,042

## Abstract

Abstract
While over 90% of patients with metastatic prostate cancer respond to systemic therapies that block androgen
receptor signaling, nearly all of these patients will eventually relapse and die due to development of acquired
therapy resistance. Thus, strategies to prevent acquired therapy resistance are needed. We have identified a
rare molecular subtype of prostate cancer with isocitrate dehydrogenase 1 (IDH1) mutation that fails to acquire
resistance to therapy. This exploratory proposal will investigate mechanisms by which IDH1-mutant prostate
cancer fails to acquire resistance to therapy with a goal to identify novel therapeutic targets to prevent resistance.
Molecular consequences of IDH1 mutation in cancer have been previously studied in AML and glioma where it
has been shown that IDH1 mutation leads to accumulation of R-2HG, inhibition of 2OG dioxygenases, increased
DNA and histone methylation, and marked alteration of epigenetic regulation of gene transcription. However,
AML and glioma are different from most solid tumors including prostate cancer because they do not metastasize
and have unique treatment paradigms. We will test the hypothesis that IDH1-mutant prostate cancer is restricted
in epigenetic control of gene transcription, rendering it less able to adapt to stress such as therapy, and that
inhibition of a 2OG-dioxygenase(s) enhances response to therapy. In Aim 1 we will study the largest cohort of
patients with IDH1-mutant prostate cancer to date to describe clinical, genomic, and transcriptomic features of
this disease. Aim 2 is to develop a transgenic murine model of IDH1-mt prostate cancer to study mechanisms of
therapy resistance and sensitivity in vivo. In Aim 3, we will perform a targeted CRISPR-KO screen to identify
2OG-dioxygenases that upon deletion increase DNA methylation and therapy sensitivity in prostate cancer.
Together, these aims will provide insight into molecular consequences of IDH1 mutation in prostate cancer and
may identify novel drug targets to disable epigenetic plasticity required for acquired resistance to therapy.

## Key facts

- **NIH application ID:** 10947087
- **Project number:** 1R21CA292179-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Laura A. Sena
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $421,042
- **Award type:** 1
- **Project period:** 2024-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10947087

## Citation

> US National Institutes of Health, RePORTER application 10947087, A study of IDH1-mutant prostate cancer to identify novel therapeutic targets (1R21CA292179-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10947087. Licensed CC0.

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