Targeting cancer cell metabolism in pancreatic adenocarcinoma

// Romain Cohen 1 , Cindy Neuzillet 1, 2 , Annemilaï Tijeras-Raballand 3 , Sandrine Faivre 4 , Armand de Gramont 5 , Eric Raymond 4 1 INSERM U728, Beaujon University Hospital (AP-HP – PRES Paris 7 Diderot), Clichy La Garenne, France 2 Department of Medical Oncology, Henri Mondor University Hospital, Créteil, France 3 AAREC Filia Research, Translational Department, Boulogne-Billancourt, France 4 Medical Oncology, Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland 5 New Drug Evaluation Laboratory, Centre of Experimental Therapeutics and Medical Oncology, Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland Correspondence to: Eric Raymond, e-mail: eric.raymond@chuv.ch Keywords: glycolysis, warburg effect, metformin, glutamine, hypoxia Received: March 08, 2015      Accepted: May 29, 2015      Published: June 10, 2015 ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is expected to become the second leading cause of cancer death by 2030. Current therapeutic options are limited, warranting an urgent need to explore innovative treatment strategies. Due to specific microenvironment constraints including an extensive desmoplastic stroma reaction, PDAC faces major metabolic challenges, principally hypoxia and nutrient deprivation. Their connection with oncogenic alterations such as KRAS mutations has brought metabolic reprogramming to the forefront of PDAC therapeutic research. The Warburg effect, glutamine addiction, and autophagy stand as the most important adaptive metabolic mechanisms of cancer cells themselves, however metabolic reprogramming is also an important feature of the tumor microenvironment, having a major impact on epigenetic reprogramming and tumor cell interactions with its complex stroma. We present a comprehensive overview of the main metabolic adaptations contributing to PDAC development and progression. A review of current and future therapies targeting this range of metabolic pathways is provided.