Targeting the MLL Complex for the Development of New Therapeutics for CRPC

About Targeting the MLL Complex for the Development of New Therapeutics for CRPC

SHAOMENG-WANG-2015-CHALLENGE-AWARDARUL-CHINNAIYAN-2015-CHALLENGE-AWARD

  • The androgen receptor (AR) is the primary oncogenic driver of prostate cancer and a major therapeutic target. Patients ultimately develop resistance to AR-targeting therapies and progress to lethal castrate-resistant prostate cancer (CRPC).
  • Often, CRPC is driven by the acquisition of genomic aberrations that confer continued activation of the AR pathway. Thus, new methods for targeting AR are necessary to treat this disease state.
  • Dr. Wang, Dr. Chinnaiyan, and colleagues are studying the targeting of menin-MLL, a complex that interacts with and supports the oncogenic activities of AR. They found that blocking the interaction between menin and MLL disabled this complex from supporting AR and inhibited tumor growth. Better inhibitors and understanding of the mechanisms involved are needed for this class of compounds to become a viable treatment strategy.
  • Highly potent and selective small molecule inhibitors of the menin-MLL interaction will be developed and tested for pharmacokinetic properties, toxicity, and anti-tumor efficacy in preclinical laboratory models in preparation for entry into clinical trials. In addition, the cellular effects of menin-MLL inhibitors will be studied in order to understand the mechanisms of action of menin-MLL inhibitors in prostate cancer.

What this means for patients: Castrate-resistant prostate cancer (CRPC) is a lethal form of prostate cancer that arises when tumors develop resistance to hormonal therapies. Dr. Wang, Dr. Chinnaiyan and team are developing and testing new therapies to target the menin-MLL complex that regulates the activity of the androgen receptor (AR). If successful, this project will result in the generation of a new therapy that blocks AR activity in a novel way and will extend the lives of CRPC patients.

Principal Investigator:

Shaomeng Wang, PhD (University of Michigan) & Arul Chinnaiyan, MD, PhD (University of Michigan)

Co-investigators:

Rohit Malik, PhD (University of Michigan), Angelo Anguilar, PhD (University of Michigan), Liu Liu, PhD (University of Michigan), Chao-Yie Yang, PhD (University of Michigan)