Research Project
10381045
Abstract Limited understanding of molecular mechanisms underlying castration-resistant prostate cancer (CRPC)is a barrier to effective therapeutic development for this fatal disease. We identified the nitric oxide receptor complex, soluble guanylyl cyclase (sGC), as a novel CRPC-inhibitory target via unbiased transcriptomics screening of an emergent CRPC model developed in our lab. Analyses of human PC datasets and our preliminary results support that sGC activity is inhibited during CRPC progression from androgen-dependent PC, and that the sGC complex is oxidatively inactivated. However we find the redox-protective mechanisms induced by androgen deprivation (AD) to protect CRPC cells from apoptosis provides a therapeutic window during which sGC can be stimulated to maximal bioactivity. Thus, we hypothesize sGC activity inhibits CRPC growth and that its stimulation by clinically-approved agonists will be therapeutically beneficial in combination with standard-of-care AD. Our hypothesis is supported by our strong preclinical data showing that the FDA-approved vasodilator and sGC agonist, riociguat, reduces in vivo growth of castration-resistant xenograft tumors, decreases PSA and increases intratumoral cyclic cGMP, the product of sGC signaling and a measure of on- target riociguat efficacy. Consistent with its biological function, sGC stimulation induces robust tumor oxygenation as well as loss of the CD44 PC stem cell marker, suggesting that it destroys hypoxic stem cell niches. Castration resistance is associated with tumor hypoxia and consequent radioresistance. We find that riociguat increases the tumor-suppressive efficacy of radiation in CRPC xenograft tumors. Our objective is to comprehensively establish molecular mechanisms underlying how and why stimulating the sGC pathway limits CRPC growth and progression and to identify factors that predict anti-CRPC efficacy of sGC agonists in preclinical models. We will assess 1) how mechanisms that control sGC levels and molecular reducing partners that regenerate oxidized inactive sGC are altered in hormone-sensitive vs. castration-resistant cells, 2) how the physiologic effects of sGC bioactivity enact anti-CRPC outcomes, with consideration of hypoxia- associated PC- relevant metabolic and redox stress mechanisms, and 3) test the efficacy of sGC agonists in the spectrum of CRPC disease. Our in vitro studies will utilize robust preclinical models of emergence, growth, progression and metastatic colonization of the bone milieu. We will utilize genetic and pharmacologic means to modulate sGC expression and activity in gold standard culture models that recapitulate the relevant clinical features of CRPC and we will utilize robust subcutaneous, orthotopic and metastatic preclinical mouse models as well as patient-derived xenografts (PDXs). We will validate key molecular findings in de-identified PC patient-derived specimens including fixed and frozen tissue, serum, and plasma. Our studies will uncover novel biology underlying CRPC growth and progression, and potentially provide preclinical rationale for re-purposing sGC agonists in combinatorial treatments with standard-of-care AD.
