R01CA257811

PSMA's Enzymatic Activity as New Target for Prostate Cancer Diagnosis and Therapy - 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 benchtop 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 explored in spite of its significant biological consequences. Furthermore, we also demonstrate an innovative, facile, and inexpensive ex vivo benchtop approach to diagnose, monitor PC and monitor therapy. Ultimately, this will benefit all patients with PC, particularly those with CRPC.

Sloan-Kettering Institute For Cancer Research

TO DEVELOP THE MEANS TO CURE AS MANY CANCER PATIENTS AS POSSIBLE AND TO CONTROL THE DISEASE IN THOSE PATIENTS WHO ARE NOT CURED. CANCER TREATMENT RESEARCH INCLUDES THE DEVELOPMENT AND EVALUATION OF IMPROVED METHODS OF CANCER TREATMENT THROUGH THE SUPPORT AND PERFORMANCE OF BOTH FUNDAMENTAL AND APPLIED LABORATORY AND CLINICAL RESEARCH. RESEARCH IS SUPPORTED IN THE DISCOVERY, DEVELOPMENT, AND CLINICAL TESTING OF ALL MODES OF THERAPY INCLUDING: SURGERY, RADIOTHERAPY, CHEMOTHERAPY, AND BIOLOGICAL THERAPY INCLUDING MOLECULARLY TARGETED THERAPIES, BOTH INDIVIDUALLY AND IN COMBINATION. IN ADDITION, RESEARCH IS CARRIED OUT IN AREAS OF NUTRITIONAL SUPPORT, STEM CELL AND BONE MARROW TRANSPLANTATION, IMAGE GUIDED THERAPIES AND STUDIES TO REDUCE TOXICITY OF CYTOTOXIC THERAPIES, AND OTHER METHODS OF SUPPORTIVE CARE THAT MAY SUPPLEMENT AND ENHANCE PRIMARY TREATMENT. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.395 - Cancer Treatment Research

National Cancer Institute (NCI) [HHS - NIH]

New York, New York 100656007 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 391% from $734,548 to $3,606,632.