Novel Androgen Receptor Degraders to Treat Castration Resistant Prostate Cancer

DESCRIPTION provided by applicant The overall aim of this grant is to generate data to understand and enable the development of a novel therapeutic approach for the treatment of patients with castration resistant prostate cancer Prostate cancer is the third most lethal cancer in the US with new cases and deaths projected to occur in While early detection surgery and hormone deprivation therapies are effective about of localized prostate cancer eventually becomes metastatic castrate resistant prostate cancer mCRPC The major driver of mCRPC is the androgen receptor AR as evidenced by the rise in the circulating levels of the AR target gene prostate specific antigen PSA Patients with these cancers treated with first generation anti androgens flutamide and bicalutamide as well as the second generation anti androgen agents enzalutamide and abiraterone have increased survival but the majority of mCRPCs also develop resistance to these agents Given the central role of AR in prostate cancer agents that target AR with a unique mode of action are urgently needed One approach is to use small molecules to degrade AR We used a novel and innovative approach that employs bi functional small molecules to bind and actively ubiquitinate and degrade AR proteins In preliminary studies these molecules called AR PROTACs have been shown to be potent selective and efficacious in both cell and animals studies A clinical candidate molecule has been chosen to advance towards clinical trials The goals of this grant support that process in several ways they aim to establish the PK PD efficacy relationship for the clinical candidate to demonstrate that this AR PROTAC inhibits the growth of mCRPC tumors that are resistant to current therapy and to conduct Investigational New Drug IND enabling studies on the clinical candidate Taken together these studies will enable a novel agent to move into clinical trials for patients with mCRPC with a good awareness about its manufacture and safety with a clear understanding of how to use this novel therapy and mostly importantly with knowledge of which patients are likely to derive benefit from this new therapy PUBLIC HEALTH RELEVANCE Despite better therapeutic options in the fight against prostate cancer progression to metastatic castration resistant prostate cancer mCRPC remains a leading cause of cancer death among men We have developed a novel therapeutic strategy for the treatment of mCRPC by designing drugs that specifically decrease the levels of the androgen receptor whose activity is linked to disease progression We believe that reducing the levels of this receptor in prostate cancer cells will create a meaningful clinical benefit when compared to blocking the receptorandapos s activity using the currently approved standard of care drugs