Androgen deprivation therapy is initially highly effective, resulting in a brief spike of apoptosis followed by a sustained G0 arrest.1 We previously investigated the molecular underpinnings of this phenomenon in vitro, showing that the majority of hormone-sensitive LNCaP and LAPC4 prostate cancer cells enter a state of androgen deprivation induced senescence or ADIS.2 As part of this study, we developed a novel method of isolating the earliest CRPC clones that are able to escape this senescent state.2
Transcriptomic analysis of these early CRPC clones revealed several altered targets in the redox regulatory space, some of which were enriched during progression to castration resistance.3 However, we found that signatures associated with several components of vasodilatory signaling were decreased in the emergent castration-resistant clones. Among these altered targets, we chose soluble guanylyl cyclase (sGC) for further exploration as its downregulation in emergent CRPC suggested that direct targeting would produce a desired CRPC-inhibitory effect, and due to the availability of an FDA-approved sGC agonist, riociguat (Adempas), a well-tolerated treatment for pulmonary arterial hypertension.
sGC is an obligate heterodimer and the primary receptor for nitric oxide. The binding of nitric oxide activates the catalytic component of sGC and triggers the conversion of 5’GTP to cyclic GMP. Increased cyclic cGMP has several known downstream effects including vasodilation as well as anti-inflammatory and anti-tissue remodeling roles. Prior studies in prostate cancer suggested that inhibiting the sGC complex would have tumor-suppressive outcomes. However, our analyses of cancer cell dependencies across multiple lines, including some used in these earlier studies, indicated that cancer cells are not dependent on sGC (depmap.org). Moreover, in vitro studies in breast and glioma cells supported our idea that sGC stimulation is likely to have tumor-inhibitory effects,4,5 consistent with the lack of any reported neoplasia with sustained use of riociguat and other sGC agonists.
Our 2024 Cancer Research publication6 describes in vitro and in vivo studies modulating sGC expression and activity through genetic and pharmacologic means in prostate cancer cells. Molecular analyses supported that androgen deprivation enhances the anti-tumor effects of riociguat by maintaining sGC in its functional and active state. Stimulating sGC signaling via riociguat in the castrate setting resulted in increased intratumoral and plasma cGMP. The degree of cGMP elevation correlated significantly with the extent of tumor suppression. Endpoint analysis of riociguat-treated tumors demonstrated increased apoptosis, improved blood vessel canalisation, and decreased hypoxia as well as loss of the prostate cancer stem cell marker, CD44. Moreover, through its improved tumor oxygenation, riociguat treatment increased the efficacy of radiation in limiting growth of castration-resistant tumors.
In addition to preclinical testing of riociguat’s ability to decrease castration-resistant tumor burden, as part of our initial analysis to confirm that this pathway is truly downregulated in clinical CRPC, we analyzed patient-matched serum samples from the CSPC and CRPC state.
Although the sample size was small (n=10), nearly all patients demonstrated decreased cGMP levels in the CRPC state, from their castration-sensitive baseline. The one patient who actually had a rise in cGMP levels demonstrated a more indolent disease course and lived far beyond the median overall survival. Patients with more dramatic cGMP suppression had more aggressive disease courses with shorter than expected overall survival times. While these numbers are small, this strong correlation warrants further exploration of sGC suppression and low circulating cGMP levels as a predictive biomarker for aggressive CRPC.
Overall, our study provides the rationale for pursuing clinical trials exploring the efficacy of riociguat in controlling CRPC. We found no systemic toxicities in our study animals.
Moreover, riociguat use in humans is associated with relatively minor adverse drug effects, consistent with the initial clinical Phase 3 studies conducted internationally.7 Therefore, we do not expect to see significant toxicities with riociguat use in future CRPC trials. There are several clinically-tested or approved drugs in the sGC agonist armamentarium, and our studies open the possibility of expanded oncologic repurposing in this space. In our publication,6 we also showed enhancement of sGC activity by cinaciguat, an sGC activator that works only on oxidized sGC, found to a higher extent in castration-resistant tumor cells versus their hormone-sensitive counterparts. Cinaciguat was not developed beyond Phase 1 for use in humans due to significant toxicity, however, other sGC activators are in various stages of clinical development. Vericiguat is another recently FDA-approved sGC stimulator, which is expected to have a similar mode of action as riociguat and may allow for therapeutic on-target stimulation without toxic systemic side effects. Our study has thus established key models, methodologies, and biomarkers for preclinical testing of this novel class of vasodilatory agents in oncology settings.
Written by: Janaki Sharma,1,3 Marijo Bilusic,1,3 Priyamvada Rai2,3
- Department of Medicine/Medical Oncology, University of Miami Miller School of Medicine, Miami, FL
- Department of Radiation Oncology, Division of Biology, University of Miami Miller School of Medicine, Miami, FL
- Sylvester Comprehensive Cancer Center, Miami, FL
- Harris WP, Mostaghel EA, Nelson PS, et al. Androgen deprivation therapy: progress in understanding mechanisms of resistance and optimizing androgen depletion. Nat Clin Pract Urol 2009;6(2):76-85. doi: 10.1038/ncpuro1296
- Burton DG, Giribaldi MG, Munoz A, et al. Androgen deprivation-induced senescence promotes outgrowth of androgen-refractory prostate cancer cells. PLoS One 2013;8(6):e68003. doi: 10.1371/journal.pone.0068003
- Samaranayake GJ, Troccoli CI, Huynh M, et al. Thioredoxin-1 protects against androgen receptor-induced redox vulnerability in castration-resistant prostate cancer. Nat Commun 2017;8(1):1204. doi: 10.1038/s41467-017-01269-x [published Online First: 2017/11/02]
- Wen HC, Chuu CP, Chen CY, et al. Elevation of soluble guanylate cyclase suppresses proliferation and survival of human breast cancer cells. PLoS One 2015;10(4):e0125518. doi: 10.1371/journal.pone.0125518 [published Online First: 20150430]
- Zhu H, Li JT, Zheng F, et al. Restoring soluble guanylyl cyclase expression and function blocks the aggressive course of glioma. Mol Pharmacol 2011;80(6):1076-84. doi: 10.1124/mol.111.073585 [published Online First: 2011/09/13]
- Zhang L, Troccoli CI, Mateo-Victoriano B, et al. Stimulating Soluble Guanylyl Cyclase with the Clinical Agonist Riociguat Restrains the Development and Progression of Castration-Resistant Prostate Cancer. Cancer Res 2025;85(1):134-53. doi: 10.1158/0008-5472.CAN-24-0133
- Tanabe N, Ogo T, Hatano M, et al. Safety and effectiveness of riociguat for chronic thromboembolic pulmonary hypertension in real-world clinical practice: interim data from post-marketing surveillance in Japan. Pulm Circ 2020;10(3):2045894020938986. doi: 10.1177/2045894020938986 [published Online First: 20200723]