Development of a CBP/p300 Degrader for the Treatment of Castra-tion-Resistant Prostate Cancer

Principal Investigators: Arul Chinnaiyan, MD, PhD (University of Michigan), Shaomeng Wang, PhD (University of Michigan), Ulka Vaishampayan, MBBS (University of Michigan), Abhijit Parolia, PhD (University of Michigan)

Young Investigator: Jie Luo, PhD (University of Michigan)

Co-Investigators: Jeremy Taylor, PhD (University of Michigan), Yuanyuan Qiao, PhD (University of Michigan)

Description: During prostate cancer progression, tumor cells become dependent on an aberrant genomic 3D organization that enables high expression of critical oncogenes.

Two key proteins that regulate this process are CBP and p300. Preclinical studies have shown that CBP/p300 inhibitors can decrease oncogenic signaling pathways and inhibit prostate cancer tumor growth in animal models. However, previously developed CBP/p300 inhibitors are unable to fully inhibit the proteins, and subpar activity has been seen in clinical trials.

Chinnaiyan and team are developing a new class of drugs, called PROTACs, that target CBP/p300 and cause complete degradation of these proteins.

The team has already developed an oral treatment candidate CB-P/p300-PROTAC called CBPD-409.

In this project, the team will determine the mechanism of action of CB-PD-409, comprehensively profile its efficacy in preclinical models of cas-tration-resistant prostate cancer (CRPC), and perform correlative studies in a phase 1/2 clinical trial of CBPD-409 alone and in combination with en-zalutamide in metastatic CRPC patients.

If successful, this project will identify the mechanism of action of CB-P/p300-PROTACs and determine features of prostate cancer cells that make them more susceptible to this therapy. These studies will also position CBPD-409 for further clinical development and highlight the potential of CBP/p300 degraders as new treatment options for mCRPC.

What this means to patients: New and more effective treatments are needed for mCRPC. Dr. Chinnaiyan and team are developing a new therapy that targets and fully degrades the prostate cancer oncogenes CBP and p300. This project will provide preclinical data for the efficacy of this new treatment, and analyze biomarkers of response from a phase 1/2 clinical trial in mCRPC patients, paving the way for further clinical development and a new treatment for mCRPC.