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 220,000 new cases and 27,000 deaths projected to occur in 2015. While early detection, surgery and hormone deprivation therapies are effective, about 10-20% 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 Statement: 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 receptor's activity using the currently approved standard of care drugs.
Project Terms: abiraterone; Androgen Antagonists; Androgen Receptor; Androgens; Animals; Area; Awareness; Bicalutamide; Binding (Molecular Function); Cancer Etiology; Cancer Patient; castration resistant prostate cancer; Cells; cellular engineering; Cessation of life; Chemicals; Chemistry; Chimera organism; Clinical; Clinical Chemistry; Clinical Trials; Data; deprivation; Development; Disease; Disease Progression; Dose; Drug Design; Early Diagnosis; effective therapy; fight against; Flutamide; Formulation; Gene Targeting; Generations; Goals; Grant; Growth; head-to-head comparison; Hematology; Hormones; improved; In Vitro; innovation; intravenous injection; Investigational Drugs; Knowledge; Link; LNCaP; Malignant neoplasm of prostate; Malignant Neoplasms; Measurement; men; Metastatic to; Mus; novel; novel therapeutic intervention; novel therapeutics; Operative Surgical Procedures; Patients; Pharmaceutical Preparations; Pharmacodynamics; pre-clinical; Process; Property; prostate cancer cell; Prostate-Specific Antigen; Proteins; Proteolysis; public health relevance; receptor; Receptor Signaling; Recovery; Resistance; Resistance development; response; Rodent; Role; Route; Safety; safety study; Schedule; SCID Mice; Sequential Treatment; Serum; small molecule; Solubility; standard of care; Subcutaneous Injections; targeted agent; Therapeutic; Time; Toxicology; treatment strategy; tumor; tumor growth; tumor progression; tumor xenograft; VCaP; Xenograft Model
