# PSMA’s enzymatic activity as new target for Prostate Cancer diagnosis and therapy

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2024 · $697,822

## Abstract

SUMMARY. The problem: Hormone therapy remains the standard treatment for prostate cancer (PC). While
most patients initially respond to therapy, they will ultimately progress to lethal castration-resistant PC (CRPC)
within 6 to 12 months. During progression, canonical sources of androgens are replaced with mechanisms that
trigger PC growth, even in the absence of hormones, making therapy at this stage very difficult. Proposed
solution: We will utilize a newly discovered biological function of prostate-specific membrane antigen (PSMA)
to develop an entirely new personalized therapeutic strategy for PC that is significantly different from existing
therapies. High levels of PSMA are seen in most aggressive forms of PC and are a predictor for progression.
However, the biological role of PSMA remains unknown. Our proposal is based on our recent paradigm-shifting
discovery that PSMA provides a so far unknown oncogenic signaling function, where its enzymatic activity
triggers an intricate intracellular signaling repertoire, promoting cancer growth through activation of the
Pi3K/AKT/mTORC-1 as well as the mTORC-2 signaling cascades. Having charted the interface of PSMA with
the main biological signaling cascades in PC, we provide here a novel therapy that disrupts these major signaling
pathways. Importantly, inhibition of PSMA led to a survival benefit in mice. We developed in parallel a companion
imaging assay to diagnose and monitor PC with a cheap and facile ex vivo bioluminescence-based assay from
readily available samples. In this assay glutamated luciferein (GluLuc) is cleaved specifically by PSMA to release
luciferin that can be detected by luciferase in urine/prostatic secretions with a bench top assay system. We have
already evaluated this assay in mice and patients and have shown that it is superior to the gold standard of PSA
levels. Here, Aim 1 will focus on our companion imaging assay. We will measure luciferin released by PSMA in
expressed prostatic secretions urine (EPS/U) or urine and correlate the bioluminescence signal with local and
metastatic tumor burden and growth. Aim 2 will explore inhibition of PSMA as therapy for PC as monotherapy or
in combination with androgen inhibition. Since inhibition of PSMA activity will lead to reduced release of luciferin,
we will correlate the reduction of signal with the tumor response. We will repurpose PSMA inhibitors, with a
proven safety profile for CNS disease that were abandoned due to low CNS penetration. In Aim 3, we will explore
if PSMA inhibition can be used as therapy of CRPC and to prevent metastasis formation. We will also test if it
can delay onset of castration resistance. As in Aim 2, we will monitor therapy with the benchtop assay. Tumor
growth will be interrogated with MR and PET imaging Our work is significant, as it charts an entirely new path
for PC therapy based on the specific biological function of PSMA. The underlying biology of PSMA is highly
innovative, as it has never been...

## Key facts

- **NIH application ID:** 10877944
- **Project number:** 5R01CA257811-04
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Brett Stewart Carver
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $697,822
- **Award type:** 5
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10877944

## Citation

> US National Institutes of Health, RePORTER application 10877944, PSMA’s enzymatic activity as new target for Prostate Cancer diagnosis and therapy (5R01CA257811-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10877944. Licensed CC0.

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