174P - Unlocking the potential of blood-based biomarkers in pancreatic cancer for early detection and therapeutic screening

Background

Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival of <12%. Patients typically present with advanced disease. Developing a blood-based screening panel could offer a simple test without requiring invasive procedures, enabling earlier detection and accelerate drug discovery. This study integrated plasma-based proteomic, tissue and clinical data supported by the PURPLE pancreatic cancer registry to identify novel biomarkers that can aid screening for early-stage disease, predict survival outcomes and guide drug discovery.

Methods

Unbiased quantitative comparative proteomics analysis was performed via a 16-window diaPASEF method on a TIMS TOF Pro mass spectrometer. Data was searched with DIA-NN (v1.8.3) in library-free mode and normalisation using RUVIIIC (v1.0.19). Matched clinicopathological and survival data was extracted from the PURPLE pancreatic cancer registry.

Results

Proteomic analysis of plasma from 203 participants showed distinct protein changes between PDAC patients with early and late-disease stage. Plasma from 120 PDAC, 69 healthy controls and 14 alternative pancreatic pathologies were analysed. A total of 919 proteins were detected (mean of 400 in each sample). When comparing PDAC with healthy controls, 246 significant differentially expressed proteins were identified (false discovery rate, FDR <0.1). Hierarchical data clustering analysis demonstrated a clear protein signature of the top 40 differentially expressed proteins in PDAC. When comparing early versus late-stage PDAC, 12 significantly differentially expressed proteins were identified. Reactome pathway analysis revealed significant up-regulation in immune response and wound healing pathways, and down-regulation of lipid and glucose metabolism in PDAC. These findings suggest that abnormal processes are quantifiable and can be detected earlier in the blood.

Conclusions

A unique PDAC protein signature was identified when comparing PDAC to healthy controls and alternative pancreatic pathologies. The dysregulated proteins identified have potential therapeutic implications that could accelerate selection of drug targets, inform clinical trial design, and enable earlier blood-based PDAC screening.

Clinical trial identification

Australian New Zealand Clinical Trial Registy Trial Acronym: PURPLE Registry Pancreatic cancer: Understanding Routine Practice and Lifting End Results (PURPLE). A Prospective Pancreatic Cancer Clinical Registry Registration number: ACTRN12617001474347 Registered: 08/03/2017.

Editorial acknowledgement

Legal entity responsible for the study

Walter & Eliza Hall Institute.

Funding

Hemstritch Centenary Fellowship ( Awarded to Dr Belinda Lee), Philanthropic funding from the Hemstritch Foundation & Segal Foundation.

Disclosure

All authors have declared no conflicts of interest.