# Inflammatory and Mitochondrial Plasticity in Neuroendocrine Prostate Cancer

> **NIH CA P01** · THOMAS JEFFERSON UNIVERSITY · 2026 · $531,281

## Abstract

PROJECT SUMMARY
Potent antagonists of androgen and androgen receptor (AR) signaling have revolutionized the treatment of
recurrent prostate cancer (PrCa). Despite initial responses, all patients eventually become resistant to
treatment, but in approximately 20% of the cases, and perhaps more, the disease evolves in response to
therapy to a new, rapidly progressing and diffusely metastatic neuroendocrine prostate cancer (NEPC), with a
life expectancy of 7 months or less. NEPC is not merely a case of treatment resistance. Instead, it is the result
of the extraordinary plasticity of tumor cells that adapt to the evolutionary pressure imposed by drug treatment
to change lineage specification, lose AR dependence, modulate transcriptional networks, and acquire new
traits of heightened cell invasion and metastasis. Fully integrated with the other components of this Program,
Project 2 has now identified two novel determinants of NEPC plasticity that drive metastatic disease. We found
that exposure to androgen-deprivation therapy triggers unrestrained transcription and increased production of
the proinflammatory cytokine, interleukin-1β (IL-1β), resulting in increased PrCa motility, skeletal metastases
and reprogramming of the bone metastatic microenvironment, in vivo. In addition, these NEPC metastases
exhibit persistent mitochondrial dysfunction due to reduced levels of the organelle scaffolding protein, Mic60. In
turn, these Mic60-low mitochondria become multifunctional signaling hubs in NEPC: they activate a pro-
survival endoplasmic reticulum (ER) stress response, upregulate an immune-inflammatory transcriptome, and
reprogram metabolism to fuel increased tumor cell invasion and metastasis. Pharmacologic or genetic
targeting of this pathway restores tumor cell killing and suppresses NEPC, in vivo. Therefore, the hypothesis
that deregulated IL-1β production and Mic60-low mitochondrial signaling are novel determinants of
therapy-induced metastatic NEPC and actionable thera

## Key facts

- **NIH application ID:** 11265632
- **Project number:** 1P01CA298993-01A1
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Dario C Altieri
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** CA
- **Fiscal year:** 2026
- **Award amount:** $531,281
- **Award type:** 1
- **Project period:** 2026-03-06T00:00:00 → 2031-02-28T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11265632

## Citation

> US National Institutes of Health, RePORTER application 11265632, Inflammatory and Mitochondrial Plasticity in Neuroendocrine Prostate Cancer (1P01CA298993-01A1). Retrieved via AI Analytics 2026-05-17 from https://api.ai-analytics.org/grant/nih/11265632. Licensed CC0.

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