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2025 Joel Holsinger – PCF Young Investigator Award

Developing a Dual PROTAC-type Degrader Platform for Simultaneous AR and GR Degradation Against Lethal Prostate Cancer

Su Deng, PhD
Yale University

Mentors: Ping Mu; Uttam Tambar

Description:

  • Metastatic Castration-Resistant Prostate Cancer (mCRPC) is the deadliest form of prostate cancer, with a 5-year survival rate of merely 28%. Though mCRPC is often treated with androgen receptor (AR) targeted therapy, such as enzalutamide, resistance to this therapy is inevitable, underscoring the unmet need to develop novel therapeutic approaches to overcome resistance.
  • During Dr. Deng’s postdoctoral training at UT Southwestern Medical Center, she and her colleagues identified a novel molecular subtype of mCRPC, classified by reduced levels of the protein CHD1, which responds poorly to AR-targeted therapy and occurs in 15-35% of patients. Over 60% of these resistant tumors exhibit abnormal activation of the glucocorticoid receptor (GR) and restoration of AR signaling, suggesting GR may be a promising therapeutic target for this subset of mCRPC. 
  • In this project, Dr. Deng and her team will develop a novel Dual-target Proteolysis Targeting Chimeric (PROTAC)-based protein degrader platform, and develop Dual-PROTACs that simultaneously target both GR and AR. PROTACs are a newer class of cancer therapies that cause degradation of the cancer proteins they target.
  • Dr. Deng will use the high-throughput PROTAC synthesis platform to develop a series of GR-PROTACs, and validate their ability to target and degrade GR. Dual-PROTACs that target both AR and GR will then be developed and validated in clinically relevant mCRPC models.
  • If successful, this project will develop a first-in-class GR+AR dual-degrader able to overcome AR therapy resistance, which could significantly improve clinical outcomes for patients with lethal prostate cancer. Additionally, the dual-PROTAC platform holds promise for targeting a wide range of oncogenic drivers in prostate cancer and has potential applications in addressing therapy resistance in other cancers, such as breast and lung cancers.

What this means to patients: Resistance to AR-targeted therapies is nearly universal in advanced prostate cancers, making critical the need to identify new treatments that prevent or overcome therapy resistance.  Dr. Deng’s project will develop a novel GR+AR dual-degrader therapy and validate this in preclinical studies, readying it for testing in clinical trials. This could lead to a new treatment for this currently lethal disease state.