From Bench to Bedside: Structural and Biological Barriers to Therapeutic Translation in Pancreatic Cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers, driven largely by KRAS mutations and profound therapeutic resistance. This review summarizes recent translational strategies aimed at bridging laboratory discoveries with clinical application, including precision oncology, rational combination therapies, and stromal modulation. We examine preclinical and clinical studies that highlight mechanistic insights such as KRAS inhibition, PARP-targeted therapy, and multi-drug regimens, drawing lessons from genetically engineered mouse models, patient-derived xenografts, and biomarker-guided clinical trials. Recent advances demonstrate that previously undruggable targets, including KRAS, can now be modulated using mutation-specific inhibitors and combination therapies, achieving complete tumor regression in preclinical models. PARP inhibitors in BRCA-mutated PDAC exemplify the translation of precision medicine into patient benefit. Adaptive, biomarker-driven trials enhance the detection of therapeutic signals, while stromal reprogramming improves drug delivery and immune accessibility. Artificial intelligence and systems biology further support predictive modeling and optimization of trial design. Overall, translational research in PDAC shows that persistent mechanistic exploration, combination strategies, and innovative trial designs can overcome historical therapeutic barriers. Despite systemic challenges such as funding, regulatory hurdles, and structural limitations, these approaches provide a roadmap for improving clinical outcomes. Continued interdisciplinary collaboration and precision-guided interventions will be essential to fully realize the potential of these discoveries.