# Role and targeting of PRMT5 in prostate cancer

> **NIH NIH R01** · PURDUE UNIVERSITY · 2021 · $504,707

## Abstract

Prostate cancer is the second leading cause of cancer death among American men. The objective of this
project is to develop a novel therapeutic approach to treat prostate cancer by overcoming the mechanisms of
resistance. Androgen receptor (AR) signaling drives prostate cancer development and progression, and
androgen deprivation therapy (ADT) is the standard of care for locally advanced and metastatic hormone naïve
prostate cancer (HNPC). Unfortunately, most patients develop castration resistant prostate cancer (CRPC)
within 2-3 years via AR reactivation (e.g., AR overexpression, AR mutations, AR splice variants), which is also
the mechanism of resistance to the two next generation anti-AR signaling inhibitors (ASI) abiraterone and
enzalutamide. Further, all of these agents induce the development of AR negative neuroendocrine prostate
cancer (NEPC), which constitutes approximately 25% of CRPC cases, a lethal and late stage of prostate
cancer without any treatment option. Thus, there is an urgent need to develop novel targeting approaches for
prostate cancer treatment. Protein arginine methyltransferase 5 (PRMT5) is an emerging oncogene that often
epigenetically represses transcription of target genes such as tumor suppressors and cell cycle inhibitors in
cancer cells. Preliminary findings show that PRMT5 promotes prostate cancer cell growth in vitro and in vivo
via epigenetic activation of AR transcription in both HNPC and CRPC cells. Unlike ADT and ASI, PRMT5
inhibition by our novel inhibitor does not induce NEPC development in prostate cancer cells using our in vitro
model system. Given that AR transcription precedes AR splicing and the translation of wild-type and mutant
AR proteins, we hypothesize that targeting PRMT5 will offer an effective and unique treatment approach for
prostate cancer by overcoming the mechanisms of AR reactivation without inducing NEPC development. To
test this hypothesis, we will pursue the following aims. Aim 1 will determine the role of PRMT5 in regulating AR
expression and cell growth in CRPC cell lines. Aim 2 will elucidate the epigenetic mechanism by which PRMT5
regulates AR transcription and cell growth as well neuroendocrine differentiation. Aim 3 will evaluate whether
PRMT5 targeting demonstrates a better treatment effect for both HNPC and CRPC in animal models. Aim 4
will improve the potency and pharmacokinetic properties of PRMT5 inhibitors while preserving its specificity for
prostate cancer preclinical studies.
 Impact: Successful completion of proposed research will gain mechanistic insight into how PRMT5
epigenetically regulates AR transcription in prostate cancer cells and will provide preclinical evidence that
targeting PRMT5 is an effective approach for treatment of both HNPC and CRPC without inducing NEPC
development. Further improvement and identification of potent and specific PRMT5 inhibitors will likely lead to
the development of PRMT5 inhibitors for future clinical trials.

## Key facts

- **NIH application ID:** 10162523
- **Project number:** 5R01CA212403-05
- **Recipient organization:** PURDUE UNIVERSITY
- **Principal Investigator:** Jiaoti Huang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $504,707
- **Award type:** 5
- **Project period:** 2017-06-09 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10162523

## Citation

> US National Institutes of Health, RePORTER application 10162523, Role and targeting of PRMT5 in prostate cancer (5R01CA212403-05). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10162523. Licensed CC0.

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