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 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 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.