Integrative proteomic profiling in high-grade serous ovarian carcinoma: Unraveling biomarkers and therapeutic targets

BackgroundHigh-Grade Serous Ovarian Carcinoma (HGSOC) is a significant clinical challenge with a 30% five-year survival rate and limited targeted therapy options, primarily PARP inhibitors benefiting only ∼10% of patients with BRCA mutations. Consequently, there is a pressing need for novel prognostic biomarkers and therapeutic targets to enhance patient stratification.MethodsWe conducted comprehensive mass spectrometry based proteomic and phosphoproteomic analyses of archived matched fresh frozen (FF) and formalin-fixed paraffin-embedded (FFPE) tissues from 24 HGSOC patients. Tissue samples underwent macrodissection into tumor-rich and tumor microenvironment (TME) regions. Data was analyzed using DIANN software with a stringent 1% false discovery rate (FDR) at both protein and peptide level.ResultsThe final dataset comprised 65 samples from 24 patients resulting in 12,440 proteins and 24,139 phosphosites with a robust 95% overlap on proteomic and 55% overlap on phosphoproteomic levels. Tumor purity directed macrodissection captured tumor-TME changes in patients as a function of treatment with significant enrichment of angiogenesis, immune response and extracellular matrix (ECM) receptor interactions in TME compared to matched tumor regions (1D annotation enrichment, FDR<0.1). Unsupervised analysis identified two patient groups based on neoadjuvant chemotherapy and short relapse free survival (RFS): untreated patients enriched in proliferation signatures, and pre-treated patients characterized by immune response (Fisher Exact test, FDR<0.1). Finally, analysis of BRCA Mut and WT patients unveiled differential DNA repair processes, with a subset of WT patients showing similarities to BRCA mutant counterparts (t-test, FDR<0.1).ConclusionsOur study showcases detection of proteomic cancer vulnerabilities from archived samples, offering potential biomarkers and targets for validation. Identifying BRCA WT patients with DNA repair pathway deficiencies suggests therapeutic indication expansion beyond BRCA mutations.Legal entity responsible for the studyThe authors.FundingProtai Bio.DisclosureAll authors have declared no conflicts of interest.