Developing a minimally invasive liquid biopsy-based assay to predict and characterizetherapeutic response in a phase II clinical trial for mCRPC

About This Grant

Background: Prostate cancer (PCa) remains the most common non-cutaneous cancer in males in the US, and the leading cause of cancer-related deaths worldwide. HER2 expression has been identified as a marker for aggressive disease and serves as a potential target for precision medicine. Significance: Precision Oncology with widespread use of NextGen Sequencing has brought personalized medicine in the treatment of various cancers. Most commonly used precision therapies in PCa involve PARP inhibitors for cases with homologous recombination repair defects and immunotherapy for cases with high microsatellite instability, mismatch repair defects or high tumor mutation burden. Despite their availability, most patients remain ineligible for targeted therapy and identification of new targets for therapeutic intervention remains an unmet need. The planned phase II clinical trial to treat metastatic castration-resistant PCa (mCRPC) patients with HER2-directed ADC therapy holds relevance for Veterans' health by addressing this pressing need for effective treatments. The proposed study aims to improve identification of Veterans who might benefit from this therapy and aligns with VHA priorities for improving cancer care for Veterans and addresses gaps in precision medicine for PCa. Innovation & Impact: Utilizing a liquid biopsy platform to assess HER2 expression in mCRPC patients based on molecular profiling of ctDNA and CTCs may increase sensitivity of detection for patient selection towards HER2-directed ADC therapy. Successful implementation of this approach will likely mitigate the procedural burden on patients who may qualify for therapy. Specific Aims: 1. Validate pre-treatment CTC HER2 as a screening biomarker for HER2 expression and trial eligibility. a. Correlate the level and prevalence of HER2 cell-surface expression on CTCs to HER2 IHC b. Correlate the level of HER2 in CTC mRNA to the results of HER2 IHC c. Correlate HER2 expression with the status of HER2 gene amplification and/or mutation 2. Determine mechanisms of resistance to HER2 ADC therapy. a. Perform single cell phenotyping for HER2 protein expression at baseline, on-treatment and progression. b. Identify signaling pathways in CTCs before treatment and upon disease progression using mRNA-Seq that correlate with therapy resistance. 3. Identify signaling pathways for combinatorial therapeutic intervention to overcome resistance. Methodology: The study involves collecting samples from patients participating in a multi-site clinical trial under the VA POPCaP PATCH initiative, utilizing liquid biopsy to analyze ctDNA and CTCs. Statistical methods include paired tests, gene set enrichment analysis, and regression modeling to correlate molecular alterations with treatment response and resistance. Next Steps/Implementation: Successful completion of the above aims will result in the development of a comprehensive liquid biopsy platform to identify predictive biomarkers for therapy response and resistance. Collaboration with a CLIA-certified lab ensures reliable results and translation into clinical practice. The trial has been approved by VA Central IRB and is about to commence enrollment. Furthermore, the above approach is not only applicable to HER2-directed ADC therapies, as it may serve as a blueprint for investigating liquid biomarkers and molecular pathways in various PCa treatments and other advanced clinical trials.