Molecular and Genetic Bases of Pancreatic Cancer

Vanja      Vaccaro; Alain      Gelibter; Emilio      Bria; Pierluigi      Iapicca; Paola      Cappello; Francesca      Di Modugno; Maria      Simona Pino; Carmen      Nuzzo; Francesco      Cognetti; Francesco      Novelli; Paola      Nistico; Michele      Milella

Abstract

Pancreatic cancer remains a formidable challenge for oncologists and patients alike. Despite intensive efforts, attempts at improving survival in the past 15 years, particularly in advanced disease, have failed. This is true even with the introduction of molecularly targeted agents, chosen on the basis of their action on pathways that were supposedly important in pancreatic cancer development and progression: indeed, with the notable exception of the epidermal growth factor receptor (EGFR) inhibitor erlotinib, that has provided a minimal survival improvement when added to gemcitabine, other agents targeting EGFR, matrix metallo-proteases, farnesyl transferase, or vascular endothelial growth factor have not succeeded in improving outcomes over standard gemcitabine monotherapy for a variety of different reasons. However, recent developments in the molecular epidemiology of pancreatic cancer and an ever evolving understanding of the molecular mechanisms underlying pancreatic cancer initiation and progression raise renewed hope to find novel, relevant therapeutic targets that could be pursued in the clinical setting. In this review we focus on molecular epidemiology of pancreatic cancer, epithelial-to-mesenchymal transition and its influence on sensitivity to EGFR-targeted approaches, apoptotic pathways, hypoxia-related pathways, developmental pathways (such as the hedgehog and Notch pathways), and proteomic analysis as keys to a better understanding of pancreatic cancer biology and, most importantly, as a source of novel molecular targets to be exploited therapeutically.

Keywords: Pancreatic cancer, signaling pathways, targeted therapy, genetic, META-ANALYSIS, RANDOMIZED TRIALS, Inherited Cancer Syndromes, EGFR PATHWAY, PROTEOMICS, TRAIL