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2025 Neil Bluhm – PCF Young Investigator Award

Epigenetic Priming to Enhance PSMA Expression and Response to PSMA Targeted Therapy in PSMA-Low Metastatic Castration Resistant Prostate Cancer

Ruben Raychaudhuri, MD
Fred Hutchinson Cancer Center 

Mentors: Michael Schweizer; Michael Haffner; Peter Nelson

Description:

  • Prostate specific membrane antigen (PSMA) is a protein on the surface of prostate cancer cells that has become both a diagnostic and therapeutic target for patients with prostate cancer. 177-Lu-PSMA-617 (LuPSMA, Pluvicto®), a radioactive therapy that targets PSMA, was recently approved for patients with metastatic castration resistant prostate cancer (mCRPC). However, only ~50% of patients respond to this treatment, due in part to variable PSMA levels, being too low or not present on some tumor cells. PSMA variability in mCRPC patients underscores the need for strategies to enhance PSMA levels on prostate cancer cells to improve LuPSMA treatment efficacy.
  • One reason for low PSMA levels, is repression of the PSMA gene by epigenetic regulators – these are enzymes that alter DNA 3D structure and accessibility by adding chemical modifications to DNA. Specifically, the addition of methyl groups to DNA causes gene repression, and this has been observed on the PSMA gene in prostate cancers with low PSMA levels.
  • Dr. Ruben Raychaudhuri and team previously found that pharmacological inhibition of the epigenetic pathway enzyme histone deacetylase (HDAC) increases PSMA levels in preclinical prostate cancer models. The team is now conducting a proof-of-concept clinical trial (NCT06145633) to evaluate whether the HDAC-inhibitor, vorinostat, can increase PSMA expression in mCRPC, and improve responses to subsequent LuPSMA therapy. 
  • In this project, Dr. Raychaudhuri will assess the safety and efficacy of HDAC-inhibitor treatment for enhancing PSMA expression and subsequent LuPSMA responses in patients with mCRPC in this clinical trial. Additionally, he will define the molecular mechanisms underlying low PSMA expression in mCRPC and track epigenetic changes caused by HDAC-inhibitor treatment.
  • If successful, this project will advance understanding of prostate cancer biology, support the development of prognostic/predictive biomarkers, and result in a new therapeutic strategy to enhance efficacy of LuPSMA treatment and improve the outcomes of patients with mCRPC. 

What this means to patients: LuPSMA is one of the newest treatments for advanced prostate cancer; however, responses have been limited in patients with variable PSMA levels. Dr. Raychaudhuri and team are conducting a clinical trial to test whether and how the HDAC-inhibitor, vorinostat, can increase PSMA levels and subsequent responses to LuPSMA. This could lead to a treatment strategy to enhance the efficacy of LuPSMA and improve the outcomes of patients with prostate cancer.