# Interleukin-1beta and AR-negative tumor cells in metastatic castrate-resistant prostate cancer

> **NIH NIH R01** · DREXEL UNIVERSITY · 2022 · $389,523

## Abstract

Treatment of prostate cancer patients relies heavily on therapeutic strategies depriving tumor cells of the
transcriptional activity of the Androgen Receptor (AR). Despite their initial efficacy, androgen-deprivation
therapies (ADT) are eventually circumvented by the emergence of castrate-resistant prostate cancer (CRPC),
which is characterized by skeletal metastases in more than 90% of patients.
We have recently demonstrated that approximately 30% of bone-metastatic prostate cancer cells lack AR
(ARNeg) and express Interleukin-1β (IL-1β). Our hypothesis is that ARNeg cancer cells, by secreting IL-1β,
establish a supportive bone habitat, allows ARPos cells to withstand androgen-deprivation and AR inhibition.
Thus, a major goal of this proposal is to define the modalities by which ARNeg/IL-1β cancer cells sustain
skeletal colonization in prostate cancer under androgen-deprived conditions.
This proposal is structured in three aims: Aim 1. IL-1β involvement in ADT resistance; Aim 2. Role of bone
stroma in IL-1β induced regulation of ARPos cells; Aim 3. Regulation of IL-1β expression by AR.
The proposed studies will employ animal models of metastasis, human cell lines, PDX-derived cells and
human tissue amples to ascertain the functional role of IL-1β in skeletal colonization of prostate cancer cells,
discriminating between direct autocrine-paracrine effects on cancer cells and targeting cells of the tumor-
associated bone stroma. Furthermore, we will identify the bone stroma cells targeted by IL-1β and evaluate
three stromal factors secreted in response to IL-1β for the ability to induce AR signaling and expression of AR-
regulated genes. Finally, using a combination of molecular biology approaches we will define the mechanism
for the transcriptional regulation of IL-1β by the AR and the translational control exerted on this cytokine by
miRNAs.
Our studies will define the unique role of ARNeg prostate cancer cells in metastases and provide conceptual and
pre-clinical ground for complementary strategies to improve therapeutic outcomes.

## Key facts

- **NIH application ID:** 10366584
- **Project number:** 1R01CA259358-01A1
- **Recipient organization:** DREXEL UNIVERSITY
- **Principal Investigator:** Alessandro Fatatis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $389,523
- **Award type:** 1
- **Project period:** 2022-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10366584

## Citation

> US National Institutes of Health, RePORTER application 10366584, Interleukin-1beta and AR-negative tumor cells in metastatic castrate-resistant prostate cancer (1R01CA259358-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10366584. Licensed CC0.

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