Castration-resistant prostate cancer (CRPC) arises from a failure of standard-of-care androgen deprivation (AD) therapy to suppress emergence of castration-resistant (CR) variants from the original androgen deprivation-responsive PC (ADPC). Identifying molecular drivers of emergence is critical for developing curative therapies, which are sorely needed. We have shown AD induces cell senescence (ADIS), a permanent proliferative arrest, in ADPC (LNCaP) cells. Our work was the first to show that ADIS selects for expansion of AD-resistant quiescent subpopulations, hastening early CRPC outgrowths (termed LNCaP-SB5). These LNCaP-SB5 represent the earliest CR cells and are a unique model for evaluating acute molecular changes underlying CRPC etiology. Unbiased microarray screening comparing LNCaP-SB5 with parent LNCaP (SB0) cells shows a critical subunit of the soluble guanylate cyclase (sGC) complex, GCSa3 (gene name: GUCY1A3), is increased under AD in the ADPC cells but downregulated in their early CRPC LNCaP SB5 counterparts. Riociguat is an orally-bioavailable, FDA-approved sGC stimulator used to treat pulmonary hypertension. Using BAY41-8543, a chemical analog of riociguat, we enhanced sGC signaling in our in vitro model of prostate cancer progression and in an in vivo xenograft CRPC model. BAY41- 8543 enhanced expression of p53 and p16INK4a in ADPC LNCaP cells, suggesting enforcement of AD-induced tumor suppression and reduced xenograft CRPC tumor formation by LNCaP-SB5 and LNAI (an established CRPC variant of LNCaP) proportional to the extent by which sGC signaling was enhanced, however, treatment did not affect viability in culture, suggesting a paracrine component to tumor suppression in CRPC. Based on these findings, we hypothesize stimulation of the sGC pathway will enhance AD-associated tumor suppression and limit CRPC emergence and progression. Therefore, we propose: 1) to determine whether riociguat treatment can enhance AD durability in ADPC to prevent CRPC emergence and 2) whether and how sGC stimulation creates a hostile tumor microenvironment to limit established CRPC. Our study will potentially facilitate rapid and safe clinical repurposing of riociguat in combination with standard-of-care AD for treatment of incurable prostate cancer.
Castration-resistant prostate cancer (CRPC), a leading cause of cancer-related deaths in American men, emerges following failure of androgen deprivation (AD) therapy and leads to terminal, incurable disease. Based on my pilot data and using preclinical models, my research will evaluate whether AD combined with stimulation of soluble guanylate cyclase signaling, using an FDA-approved drug for pulmonary hypertension, can increase the durability of AD to inhibit CRPC emergence and limit established CRPC by creating a hostile tumor microenvironment. Thus my proposed research will potentially repurpose a safe and well-tolerated drug to treat the spectrum of CRPC, from incidence to progressed disease.
