Novel Therapeutic Approaches in Pancreatic Cancer Based on Genomic Alterations

Shinichi      Yachida

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and devastating disease, which is characterized by invasiveness and dissemination to the lymphatic system and distant organs. In the absence of effective screening methods considerable efforts have thus been made to identify better systemic treatments than gemcitabine, the standard of care for advanced PDAC for well over a decade. However, until now only erlotinib, an epidermal growth-factor receptor tyrosine kinase inhibitor, has demonstrated a modest survival benefit in combination with gemcitabine in a phase III clinical trial. More recently, detailed global genomic analyses have provided a snapshot of the landscape of tumor genomes by showing that they contain four high frequency mutated genes and many low frequency mutated genes that correspond to 12 core signaling pathways. Strategies to target these frequently altered genes and their pathways, or low frequency mutated genes corresponding to the “personalized genome”, offer novel therapeutic strategies. In the near future, the complete sequencing of the coding genome, together with the dramatically reduced costs of whole genome sequencing, will provide new opportunities to treat PDAC.

Keywords: Whole genome sequencing, KRAS, TP53, CDKN2A/p16, SMAD4/DPC4, hedgehog pathway, personalized genome

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