The soluble guanylyl cyclase pathway is inhibited to evade androgen deprivation-induced senescence and enable progression to castration resistance.

Castration-resistant prostate cancer (CRPC) is fatal and therapeutically under-served. We describe a novel CRPC-restraining role for the vasodilatory soluble guanylyl cyclase (sGC) pathway. We discovered that sGC subunits are dysregulated during CRPC progression and its catalytic product, cyclic GMP (cGMP), is lowered in CRPC patients. Abrogating sGC heterodimer formation in castration-sensitive prostate cancer (CSPC) cells inhibited androgen deprivation (AD)-induced senescence, and promoted castration-resistant tumor growth. We found sGC is oxidatively inactivated in CRPC. Paradoxically, AD restored sGC activity in CRPC cells through redox-protective responses evoked to protect against AD-induced oxidative stress. sGC stimulation via its FDA-approved agonist, riociguat, inhibited castration-resistant growth, and the anti-tumor response correlated with elevated cGMP, indicating on-target sGC activity. Consistent with known sGC function, riociguat improved tumor oxygenation, decreasing the PC stem cell marker, CD44, and enhancing radiation-induced tumor suppression. Our studies thus provide the first evidence for therapeutically targeting sGC via riociguat to treat CRPC. Statement of significance: Prostate cancer is the second highest cancer-related cause of death for American men. Once patients progress to castration-resistant prostate cancer, the incurable and fatal stage, there are few viable treatment options available. Here we identify and characterize a new and clinically actionable target, the soluble guanylyl cyclase complex, in castration-resistant prostate cancer. Notably we find that repurposing the FDA-approved and safely tolerated sGC agonist, riociguat, decreases castration-resistant tumor growth and re-sensitizes these tumors to radiation therapy. Thus our study provides both new biology regarding the origins of castration resistance as well as a new and viable treatment option.

Outcomes of metastatic urothelial carcinoma following discontinuation of enfortumab-vedotin.

BACKGROUND: Enfortumab vedotin (EV) is approved to treat metastatic urothelial carcinoma (mUC) following platinum and PD1/L1 inhibitors. Since the outcomes and patterns of therapy of patients following discontinuation of EV are unknown, we conducted a retrospective study to assess this issue. METHODS: Data were retrospectively obtained from patients with mUC following discontinuation of EV after prior platinum-based chemotherapy and PD1/L1 inhibitors. Objective response rate (ORR) was evaluated in those who received therapy post-EV. Statistical analyses were performed to describe the overall survival (OS) and compare patient characteristics and outcomes of those who did or did not receive treatment post-EV. RESULTS: Data were available for 63 patients from 6 institutions: 46 (73%) were male and median age was 68 years (range 43-83). The median OS was 32 weeks. Thirty-two patients (51%) received therapy after EV. The OS of those who did vs. did not receive post-EV therapy was significantly different (median 43.1 vs. 16.9 weeks, P = .015). Longer duration of prior EV therapy was associated with receipt of post-EV therapy (P = .0437) as well as OS in both the treated (P = .045) and untreated groups (P = .012). Objective response was observed in 3 of 32 patients (9.4%) who received therapy post-EV. CONCLUSION: Outcomes of patients with mUC following discontinuation of EV are dismal and only 51% received therapy after discontinuation of EV. This study identifies benchmarks for the interpretation of activity of new agents following EV and raises the hypothesis for duration of EV as a potential prognostic factor following discontinuation of EV.

Sertoli-Leydig Cell Tumor with Concurrent Rhabdomyosarcoma: Three Case Reports and a Review of the Literature.

Sertoli-Leydig Cell Tumors (SLCTs) make up <1% of all ovarian tumors and are benign or malignant, androgen-secreting tumors. Rhabdomyosarcoma (RMS) is a heterogeneous group of malignant tumors that resemble developing skeletal muscle. There have been case reports of patients with concurrent SLCT and RMS with limited treatment options. We aim to demonstrate treatment strategies used in our patients, which seemed to have prolonged survival when compared to prior case reports of patients not cured by surgical resection. Herein we describe 22 cases of SLCT with RMS elements as discussed in prior case reports and three cases from the authors' institution. Of the 19 cases from prior case reports, five were lost to follow-up and two had NED after surgical intervention. Eleven patients had recurrence and were deceased within one year. Of those patients not surgically cured, only three patients were documented as living beyond two years, all of whom received chemotherapy. The three patients presented from our institution had clinical evidence of response to chemotherapy that is traditionally used for RMS. In conclusion, chemotherapy with doxorubicin and ifosfamide has activity in patients with SLCT and RMS as does salvage chemotherapy with vincristine, irinotecan, and temozolomide.