Principal Investigators: Arul Chinnaiyan, MD, PhD (University of Michigan), Marcin Cieslik, PhD (University of Michigan), Ulka Vaishampayan, MBBS (University of Michigan), Yuzhuo Wang, PhD (University of British Columbia)

Co-Investigators: Lanbo Xiao, PhD (University of Michigan), Abhijit Parolia, PhD (University of Michigan),  Yuanyuan Qiao, PhD (University of Michigan),  Jeremy Taylor, PhD (University of Michigan).

Description: 

• The androgen receptor (AR) is the primary oncogenic driver in prostate cancer, and thus the primary therapeutic target. However, resistance to androgen deprivation therapy (ADT) and second-generation AR targeting agents like enzalutamide and abiraterone, and progression to metastatic castration resistant prostate cancer (mCRPC), is nearly inevitable. This is because prostate cancer cells commonly adapt mechanisms to maintain AR signaling, such as amplification and mutations of the AR gene.  It has recently been shown that epigenetic changes in the AR gene are also important drivers of the development of mCRPC.
• Epigenetics is the regulation of the 3D structure of DNA surrounding a gene and its regulatory regions, which causes the gene to be more or less accessible to gene expression machinery.
• SMARCA2 and SMARCA4 are two major epigenetic regulators that are commonly altered in CRPC, and are required for AR activity. Thus, SMARCA2/4 may be ideal therapeutic targets.
• Arul Chinnaiyan and team are studying the impact of targeting SMARCA2/4 as a novel treatment approach for mCRPC.
• The team has previously shown that a novel agent which causes the degradation of SMARCA2/4 has activity against CRPC cells with express AR, but not CRPC cells which do not have AR.
• In this project, the team will investigate the mechanism of action of the SMARCA2/4-degrader in AR-positive CRPC cells.
• The team will also investigate the efficacy of the SMARCA2/4-degrader alone and in combination with AR-targeting agents in pre-clinical models of CRPC.
• The team will identify candidate biomarkers that can identify patients who are more likely to benefit from treatment with the SMARCA2/4-degrader.
• Finally, the team will initiate a phase 1/2 clinical trial to test the safety and efficacy of the SMARCA2/4-degrader alone and in combination with enzalutamide in patients with mCRPC.

What this means to patients:  Despite recent advances, mCRPC remains an incurable disease state and new treatments are urgently needed.  Dr. Chinnaiyan and team have identified a set of epigenetic regulators, SMARCA2/4, that are important in the development of CRPC and have developed a novel treatment that can target these regulators.  If successful, this team will identify the mechanisms of action of this treatment, and establish efficacy in patients, which may improve outcomes for patients with mCRPC.