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2024 Michael and Lori Milken Family Foundation – PCF Young Investigator Award

Anatomical and Cellular Determinants of Intrinsic and Acquired Resistance to PSMA-Targeted Therapy

Martin Bakht, PhD
Harvard: Dana-Farber Cancer Institute

Mentor: Himisha Beltran, MD

Description:

  • Patients with metastatic castration resistant prostate cancer (mCRPC) must have a positive PSMA PET imaging test to receive the PSMA-targeted radioligand therapy (PSMA-RLT) 177Lu-PSMA-617 (Pluvicto®). However, not all patients with PSMA PET-positive disease respond to PSMA-RLT and patients ultimately progress after therapy. 
  • Resistance to PSMA-RLT is incompletely understood, but is associated with factors including liver metastases and heterogeneity of PSMA expression. 
  • Dr. Martin Bakht is studying the mechanisms that underly PSMA heterogeneity and resistance to PSMA-RLT.
  • In this project, PSMA PET and FDG PET imaging and multi-omic (transcriptomic and metabolomic) profiling will be used to study tumors that have developed resistance to PSMA-RLT in both patients and in preclinical models. 
  • How sites of metastases including the liver, and how different tumors can be PSMA-positive and PSMA-negative in the same patient, contribute to resistance to PSMA-RLT will be investigated. 
  • Whether targeting metabolic tumor features, including amino acid uptake, can overcome or delay resistance to PSMA-RLT will be tested. 
  • If successful, this study will provide new insights into how PSMA is regulated in advanced prostate cancer and will lead to novel strategies to overcome treatment resistance and ultimately improve patient outcomes for patients treated with PSMA-RLT.

What this means to patients: PSMA-RLT is a promising new class of treatments for patients with mCRPC, but not all patients respond, and those who do eventually develop resistance and progress. Dr. Martin Bakht is investigating how PSMA heterogeneity contributes to primary and acquired resistance to PSMA-RLT, and how PSMA expression is regulated by metabolic features of the tumor microenvironment. Understanding PSMA regulation and function is essential for optimizing responses to PSMA-RLT.