Investigators

Summary

About one-third of the patients treated for prostate cancer opts for surgical removal of their tumors, with the remaining undergoing external beam radiation therapy (EBRT) or brachytherapy, along with androgen deprivation therapy (ADT; e.g., Leuprolide). While irradiation destroys the majority of cancerous cells, surviving ones can become senescent and resistant to treatment with increased risk of tumor reemergence. We have preliminary data that cinaciguat, a soluble guanilate cyclase (sGC) activator, decreases Bcl-2/BAX to enhance clearance and prevent reemergence of TRAMP-C1 orthotopic tumors in irradiated mouse prostates and in culture. Cinaciguat is a heme mimetic that promotes the formation of a heterodimer capable of catalyzing the formation of cGMP. Moreover, as cinaciguat acts only on heme-free sGC which accumulates in cells experiencing high levels of oxidative/nitrosative stress, such as following EBRT, it acts locally at the tumor site without systemic side effects in normal tissue where reduced sGC-Fe2+ is responsive only to nitric oxide (NO•). We are investigating the benefits of cinaciguat in: i) decreasing the detrimental effect of sGCα1 overexpression through enhanced dimerization of sGC; ii) increases cGMP levels via heme-free sGC to decrease Bcl-2 levels and promote apoptotic clearance of senescence cells (senolytic effect) and decrease NF-κβ-mediated cytokine release to dampen the SASP (senomorphic effect); iii) acting at the tumor site to limit systemic side effects; iv) obviating the need for ADT. We are using fractionated EBRT and the androgen-sensitive, luciferase-expressing, orthotopic TRAMP-C1 prostate cancer mouse model and cultured cells to characterize the therapeutic actions of cinaciguat.