Dataset Information

Metabolic Dependencies in Pancreatic Cancer.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) is a highly lethal cancer with a long-term survival rate under 10%. Available cytotoxic chemotherapies have significant side effects, and only marginal therapeutic efficacy. FDA approved drugs currently used against PDA target DNA metabolism and DNA integrity. However, alternative metabolic targets beyond DNA may prove to be much more effective. PDA cells are forced to live within a particularly severe microenvironment characterized by relative hypovascularity, hypoxia, and nutrient deprivation. Thus, PDA cells must possess biochemical flexibility in order to adapt to austere conditions. A better understanding of the metabolic dependencies required by PDA to survive and thrive within a harsh metabolic milieu could reveal specific metabolic vulnerabilities. These molecular requirements can then be targeted therapeutically, and would likely be associated with a clinically significant therapeutic window since the normal tissue is so well-perfused with an abundant nutrient supply. Recent work has uncovered a number of promising therapeutic targets in the metabolic domain, and clinicians are already translating some of these discoveries to the clinic. In this review, we highlight mitochondria metabolism, non-canonical nutrient acquisition pathways (macropinocytosis and use of pancreatic stellate cell-derived alanine), and redox homeostasis as compelling therapeutic opportunities in the metabolic domain.

SUBMITTER: Vaziri-Gohar A

PROVIDER: S-EPMC6315177 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Metabolic Dependencies in Pancreatic Cancer.

Vaziri-Gohar Ali A Zarei Mahsa M Brody Jonathan R JR Winter Jordan M JM

Frontiers in oncology 20181212

Pancreatic ductal adenocarcinoma (PDA) is a highly lethal cancer with a long-term survival rate under 10%. Available cytotoxic chemotherapies have significant side effects, and only marginal therapeutic efficacy. FDA approved drugs currently used against PDA target DNA metabolism and DNA integrity. However, alternative metabolic targets beyond DNA may prove to be much more effective. PDA cells are forced to live within a particularly severe microenvironment characterized by relative hypovascular ...[more]

PMID: 30631752

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Project description:Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest types of cancer. A factor that contributes to the poor prognosis of the disease is the complex tumor microenvironment (TME). The PDAC TME is composed of excessive fibrosis and desmoplasia, which creates a harsh environment resulting in hypoxia and altered nutrient availability. To promote survival and proliferation in this environment, PDAC cells can reprogram glutamine (Gln) metabolism. Previous studies have demonstrated that PDAC cells use Gln to support proliferation and redox balance. However, earlier attempts to inhibit Gln metabolism using glutaminase inhibitors resulted in rapid metabolic reprogramming and ultimately therapeutic resistance. Here, we hypothesized that using a Gln analogue, such as 6-Diazo-5-oxo-L-norleucine (DON), could broadly target Gln metabolism in PDAC and prevent rapid adaptation. Indeed, DON treatment led to a significant decrease in PDAC proliferation in a dose-dependent manner, as well as a profound reduction of various metabolites involved in central carbon and nucleotide metabolism, suggesting that DON creates a metabolic crisis. In addition, we observed a significant decrease in tumor growth in various in vivo models (syngeneic, immunodeficient) using DRP-104 (sirpiglenastat), a novel pro-drug version of DON that was designed to circumvent DON associated GI toxicity and allow the therapeutic exploration of broad Gln antagonism. Mechanistically, we found that ERK signaling is increased as a compensatory mechanism through the increased activity of receptor tyrosine kinases (RTKs). Combinatorial treatment of DRP-104 and Trametinib (MEK1/2) inhibitor led to a significant increase in survival in a syngeneic model PDAC. Taken together, these pre-clinical results suggest that broadly targeting Gln metabolism could provide a new therapeutic avenue for PDAC and that the combination with an ERK signaling pathway inhibitor could further improve the therapeutic outcome.

Dataset Information

Metabolic Dependencies in Pancreatic Cancer.

Publications

Metabolic Dependencies in Pancreatic Cancer.

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