Review
Drug resistance in pancreatic cancer: Impact of altered energy metabolism

https://doi.org/10.1016/j.critrevonc.2017.03.026Get rights and content
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Abstract

Pancreatic cancer is a highly deadly disease: almost all patients develop metastases and conventional treatments have little impact on survival. Therapeutically, this tumor is poorly responsive, largely due to drug resistance. Accumulating evidence suggest that this chemoresistance is intimately linked to specific metabolic aberrations of pancreatic cancer cells, notably an increased use of glucose and the amino acid glutamine fueling anabolic processes. Altered metabolism contributes also to modulation of apoptosis, angiogenesis and drug targets, conferring a resistant phenotype. As a modality to overcome chemoresistance, a variety of experimental compounds inhibiting key metabolic pathways emerged as a promising approach to potentiate the standard treatments for pancreatic cancer in preclinical studies. These results warrant confirmation in clinical trials. Thus, this review summarizes the impact of metabolic aberrations from the perspective of drug resistance and discusses possible novel applications of metabolic inhibition for the development of more effective drugs against pancreatic cancer.

Keywords

Cancer metabolism
Drug resistance
New metabolically-targeted agents
Pancreatic cancer

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Cristoforo Grasso received his BSc from the University of Catania, Italy in 2011. In September 2015 he was admitted as MSc student at the VU University of Amsterdam in the Netherlands, where he is attending a Master in Oncology. Currently, he is performing an internship at George Town University, Lombardi Cancer Center, Washington DC, US. He works, under the supervision of Anton Wellstein M.D., on pancreatic ductal adenocarcinoma heterogeneity and conditionally reprogrammed cell culture (CRC), in order to investigate whether CRC maintains in vitro heterogeneity of the human patient tumor biopsies.

Dr. Gerrit Jansen obtained his PhD degree in Biochemistry at the State University of Utrecht, The Netherlands in 1984. From 1985 to 1990 he held a post-doctoral position at the Utrecht University Medical Center (Dept. of Oncology). In 1991 he moved to the VU University Medical Center in Amsterdam (Dept. of Medical Oncology). From 1992 to 1994 he was a recipients of a fellowship of the Royal Netherlands Academy of Arts and Sciences, which was followed by a senior postdoctoral position at the VU University Medical Center (Dept. of Medical Oncology). In 2001 he moved to the Department of Rheumatology (currently Amsterdam Rheumatology and immunology Center) at the VU University Medical Center to become head of the laboratory for experimental rheumatology. Dr. Jansen’s main research interest focuses on molecular mechanisms of drug resistance, with a special interest for resistance mechanisms to classical and experimental drugs from an anti-arthritic and anti-cancer perspective.

Dr. Elisa Giovannetti received her M.D. and Ph.D. with full marks and honours from the University of Pisa, Italy, in 2000 and 2007, respectively. Between 2001 and 2004, she worked as a clinical fellow in Pharmacology in the Department of Oncology of Pisa University, and contributed to clinical and preclinical studies on the relationship between gene expression/polymorphisms and anticancer drug response in pancreatic and lung cancer. Since 2006 she collaborated with the Laboratory Medical Oncology at VUmc, Amsterdam, to set-up a new line of research characterizing novel predictive markers of drug activity and resistance in pancreatic cancer. She successfully requested funding from the Netherlands Organisation for Scientific Research (NWO, VENI grant), the European Initiative “Marie Curie for outgoing scientist”, Italian Association for Research against Cancer (AIRC, Start-Up grant), Cancer Center Amsterdam (CCA) Foundation, and Dutch Cancer Society (KWF). She is actively involved, as elected member of the Steering Committee, in research projects within the “Pharmacology and Molecular Mechanism Group” group of the EORTC (EORTC-PAMM), as well as in studies of the European Pancreatic Club (EPC) and Italian Association for the Study of the Pancreas (AISP).