# Therapeutic targeting of a novel driver of prostate cancer progression.

> **NIH VA I01** · VA NORTHERN CALIFORNIA HEALTH CARE SYS · 2024 · —

## Abstract

Advanced prostate cancers disproportionally affect veteran populations in the US. One
key feature of the advanced diseases is the development of anti-androgen receptor
therapy resistance through a mechanism of tumor lineage plasticity, which contributes to
the lethal progression of prostate cancer. However, the mechanisms underlying the
aberration are poorly understood, which severely hinders the development of effectively
therapeutic intervention of the advanced diseases. Our preliminary studies found that a
novel reprogramming of adrenergic receptor signaling occurs in progression to lethal
forms of prostate cancer, where beta-blocker drug target gene is silenced and, in
contrast, adrenergic ligand synthesis genes, and a different member of the adrenergic
receptor family and its signaling pathway genes are induced. In line with the change,
beta-blocker displayed no significant effect on the treatment-induced neuroendocrine
prostate cancer (t-NEPC) tumors. Remarkably, small molecule antagonists of the other
adrenergic receptor developed by us and others displayed high potency in growth
inhibition of several enzalutamide-resistant /t-NEPC cell and PDX tumor models. Our
further analyses showed that the aberrant signaling stimulates programs for cancer
stem-like cell (CSC), EMT and NEPC features, with alterations of local chromatin histone
marks. Moreover, our data suggest that a chemokine receptor appears to interact with
the adrenergic receptor and facilitate the signaling. Therefore, we will take genetics,
pharmacological, functional genomics and epigenomics approaches to test the
hypotheses that reprogramming of adrenergic receptor signaling drives tumor plasticity
and therapy resistance through cross-talks and that targeting the aberrant signaling axis
is efficacious and safe for treatment of therapy-resistant, lethal forms of PCa.

## Key facts

- **NIH application ID:** 10805043
- **Project number:** 2I01BX004271-05A1
- **Recipient organization:** VA NORTHERN CALIFORNIA HEALTH CARE SYS
- **Principal Investigator:** Hongwu Chen
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2019-01-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10805043

## Citation

> US National Institutes of Health, RePORTER application 10805043, Therapeutic targeting of a novel driver of prostate cancer progression. (2I01BX004271-05A1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10805043. Licensed CC0.

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