# Multidimensional analyses to improve PSMA-RPT efficacy in mCRPC

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2023 · $528,393

## Abstract

Summary/Abstract
While prostate-specific membrane antigen-targeted radiopharmaceutical therapy (PSMA-RPT) improves the
survival of metastatic castration-resistant prostate cancer (mCRPC) patients, response rates remain
suboptimal, and relapses invariably occur in all patients. Improving therapeutic efficacy requires a better
understanding of the genetic, molecular, and immunological determinants of tumor responses to PSMA RPT.
To identify such determinants we (i) performed dosimetry studies to optimize 177Lu-PSMA-RPT activity in
prostate cancer (PCa) models; (ii) conducted global phosphoproteomic analyses of tumors from PSMA-RPT-
treated mice and revealed the upregulation of DNA damage response/repair and TP53 pathways; (iii) showed
that wild type TP53 plays an important role in mediating responses to RPT in mice; and (iv) investigated the
impact of PSMA-RPT on the tumor immune microenvironment and demonstrated that PSMA-RPT synergizes
with pharmacological activators of the cyclic GMP–AMP synthase (cGAS)/Stimulator of Interferon genes
(STING) pathway, a cytosolic DNA sensing machinery that links DNA damage with the induction of innate
immune responses via type I interferon (IFN) signaling. Relatedly, data in the literature indicate that mutant
TP53, which occurs frequently in mCRPC, interferes with the function of the cGAS/STING/IFN pathway
thereby decreasing tumor immunogenicity. Collectively, these findings led us to hypothesize that (i) 177Lu-
PSMA-RPT triggers tumor TP53 mutational status-dependent tumor and immune cell signaling alterations in
mCRPC; (ii) profiling these alterations will identify new determinants of response to PSMA-RPT; and (iii)
targeting these determinants will enhance responses to PSMA-RPT.
We will test these hypotheses via three Specific Aims leveraging an integrated platform for systematic
profiling of RPT-induced transcriptional, signaling, and immunological alterations. In Aim 1, we will identify
RPT-induced signaling alterations in the tumor cell compartment of human PSMA-expressing PCa models and
test the hypothesis that mutant TP53 impairs responses to PSMA-RPT. In Aim 2, we will employ murine PCa
models with wild-type or mutated TP53 to investigate how tumor TP53 status impacts RPT responses and
tumor immunogenicity in immunocompetent mice. We will test the hypothesis that mutant TP53 interferes with
cGAS/STING/IFN signaling in RPT-treated tumors and reduces tumor immunogenicity. In Aim 3, we will
develop novel combination therapies that enhance or restore the cGAS/STING/IFN pathway in the mCRPC
immune tumor microenvironment and improve the magnitude and durability of RPT responses via increased
tumor immunogenicity.
Successful completion of these aims will identify new connections between mCRPC TP53 mutational status,
cytosolic DNA sensing mechanisms, and tumor immunogenicity that can be leveraged to increase the efficacy
of RPT against mCRPC through rationally designed and clinically applicable combination ther...

## Key facts

- **NIH application ID:** 10637709
- **Project number:** 1R01CA279094-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** JOHANNES CZERNIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $528,393
- **Award type:** 1
- **Project period:** 2023-07-12 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10637709

## Citation

> US National Institutes of Health, RePORTER application 10637709, Multidimensional analyses to improve PSMA-RPT efficacy in mCRPC (1R01CA279094-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10637709. Licensed CC0.

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