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2024 CCPC – PCF Young Investigator Award

Serial Blood-Based Epi-genotyping of Metastatic Castration Resistant Prostate Cancer (mCRPC) to Understand Response and Resistance to Lutetium-177-PSMA-617 (Lu-PSMA) Treatment Strategies

Sofie Tolmeijer, PhD
University of British Columbia

Mentors: Alexander Wyatt, PhD, DPhil; Shahneen Sandhu, MBBS, FRACP; Louise Emmett, MD, FRACP, FAANMS, MBChB

Description:

  • Lutetium-177-PSMA-617 (Lu-PSMA) is a novel targeted therapeutic agent for metastatic castration-resistant prostate cancer (mCRPC). However, ~40% of patients with mCRPC will derive limited benefit from Lu-PSMA despite preselection based on PET-imaging. There is a pressing need to better understand who will benefit from Lu-PSMA treatment.
  • Dr. Sofie Tolmeijer’s project aims to leverage serial minimally-invasive blood samples to unravel the biology of clinical mCRPC in the context of Lu-PSMA treatment and develop blood-based biomarkers to identify mCRPC subtypes that will not benefit from Lu-PSMA.
  • This study will utilize unique access to serial blood samples from four trials studying Lu-PSMA alone or in combination with enzalutamide, olaparib, or pembrolizumab. Blood tests will include the quantification and genomic interrogation of circulating tumor DNA (ctDNA) and assays to evaluate the activity of gene expression programs.
  • Baseline blood-based genomic and phenotypic characteristics of mCRPC will be evaluated in context of PET-scan classifications and Lu-PSMA treatment outcomes.
  • Whether on-treatment blood biomarkers can predict the depth and duration of therapy response will be determined.
  • The mechanisms that drive resistance to various Lu-PSMA combination treatment strategies will be identified.
  • If successful, this project will result in a new practical and trial-testable stratification framework for Lu-PSMA treatment. This includes identification of patients who are unlikely to benefit from Lu-PSMA (or other radioligands) due to primary radio-resistance mechanisms, patients who will benefit from de-escalation, and patients who may be suitable for trials of treatment intensification (e.g. addition of other therapeutic agent), based on the genomic or phenotypic characteristics of the tumor and molecular depth of initial therapy response.

What this means to patients: Lu-PSMA is a new FDA-approved treatment for patients with mCRPC who have positive PSMA PET scans, yet a large proportion of patients who meet eligibility criteria do not benefit from therapy. Dr. Tolmeijer’s project will develop minimally-invasive blood-based biomarkers that can identify mCRPC subtypes that will not benefit from Lu-PSMA, and facilitate treatment monitoring by repeated blood tests during treatment. As blood samples are easy to obtain outside of specialized cancer centers, candidate markers are easy to implement in the clinic, increase access to precision medicine, and improve patient prioritization for Lu-PSMA, combination therapies or alternative treatment options.