# Pharmacological Jak2 inhibition to overcome androgen receptor aberrations in prostate cancer

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2024 · $564,525

## Abstract

There is an unmet medical need for development of more efficacious therapies for castrate-resistant (CR)
prostate cancer (PC). The castrate resistant state of PC is incurable and results from a failure of androgen
deprivation therapy (ADT), which targets androgen receptor (AR) activity in PC cells. This has led to development
of second-generation AR-targeted therapies that more effectively antagonize the AR ligand binding domain
(enzalutamide) or reduce androgen synthesis (abiraterone acetate). However, after AR-targeting therapies, AR
and its splice variants are still expressed at high levels and remain transcriptionally active in CRPC and drive
castrate-resistant growth, ultimately causing patient death.
 A major gap in the field is the lack of understanding of targetable mechanisms that induce persistent AR
expression and transcriptional activity in CRPC. In this mPI proposal, we will interrogate the novel concept that
Jak2-Stat5 signaling represents a critical driver of AR gene expression in PC and, therefore, pharmacological
targeting of Jak2 signaling by the new-generation Jak2 inhibitors represents a novel therapeutic strategy to eliminate
AR in CRPC. This is supported by our rigorous preliminary data showing that activation of Jak2-Stat5 signaling is a
strong inducer of the AR gene transcription leading to high AR mRNA and protein levels in PC. Likewise, inhibition
of Jak2-Stat5 signaling blocks expression of AR and AR-Vs in PC cell lines, PC xenograft tumors in vivo and in
patient-derived clinical PCs grown as explant cultures ex vivo. Collectively, these findings support the hypothesis
that activation of Jak2-Stat5 critically promotes CRPC progression by sustaining expression of AR and
constitutively active AR variants. We will pursue two aims:1) Determine the mechanisms underlying control of AR
and AR variant mRNA expression by Jak2 signaling in PC, and the overlap of the Jak2-Stat5 and AR transcriptomes;
2) Determine the efficacy of the new-generation Jak2-inhibitors Fedratinib (FED) and Pacritinib (PAC) in
eliminating AR-FL/V7/V9 mRNA and protein expression in CRPC and suppressing growth of CRPC in vitro and
in vivo.
 The proposed work is significant because it will determine the mechanisms by which Jak2-signaling drives
persistent AR expression in CRPC. Moreover, the proposed work will establish whether Jak2 inhibition by PAC and
FED can block AR expression and growth of PC resistant to AR-targeted therapy. The novelty of the proposed
concept is that Jak2 regulation of AR opens an entirely new avenue to directly control AR levels and PC growth
through pharmacological suppression with new-generation Jak2 inhibitors currently FDA-approved or in clinical
development for other purposes. These first-in-the-field studies will have near-term impact for therapy
development for CRPC patients because they are expected to establish PAC and FED as novel agents to target
AR in PC, and translate to a phase I/II clinical study in CRPC.

## Key facts

- **NIH application ID:** 11014842
- **Project number:** 7R01CA262570-03
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Scott M. Dehm
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $564,525
- **Award type:** 7
- **Project period:** 2022-03-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11014842

## Citation

> US National Institutes of Health, RePORTER application 11014842, Pharmacological Jak2 inhibition to overcome androgen receptor aberrations in prostate cancer (7R01CA262570-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/11014842. Licensed CC0.

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