Therapeutic targeting of pancreatic cancer through stromal reprogramming and malic enzyme depletion
Doctor of Philosophy
Pancreatic ductal adenocarcinoma (PDAC) or simply pancreatic cancer is one of the most lethal of all solid tumors with a relatively unchanged dismal prognosis despite decades of efforts. Surrounded by a dense fibrotic stroma, pancreatic tumor cells acquire genetic mutations and reprogrammed metabolism to survive the stress imposed by the hypoxic, oxygen- and nutrient-deprived microenvironment. Cancer-primed activated stromal cells, pancreatic stellate cells (PSCs) and cancer-associated fibroblasts (CAFs), of the tumor microenvironment promote cancer growth by enabling immune-suppression, metastasis and chemo-resistance. In chapter 1 of this manuscript, we present an overview of PDAC biology, statistics, altered metabolism and the limitations associated with the current standard of care. In Chapter 2, we propose a novel combinatorial treatment to normalize PDAC stroma and recapitulate PSCs and CAFs quiescence. We show that treatment can enhance chemo-drug intratumoral delivery and can successfully halt tumor growth both in vitro and in vivo. We next show in chapter 3 that activated and treatment-induced quiescent stromal cells exhibit differential metabolic profiles whereby quiescent stromal cells are associated with reduced Warburg Effect and lower oxidative and reductive glutamine metabolism. In addition to stromal targeting, we show in chapter 4 how the metabolic gene malic enzyme (ME)2 provides a collateral lethality framework in PDAC that can be explored to directly target cancer epithelial cells. We provide evidence supporting that the selective targeting of ME3, a ME2 isoform, could be used as a novel strategy for the therapeutic treatment of a genotype-specific subset of PDAC patients. We conclude this manuscript with chapter 5 in which we propose future studies and present directions towards finding a cure for pancreatic cancer. In summary, we provide evidence that normalizing pancreatic stroma and targeting cancer-specific altered metabolic pathways could present viable therapies for PDAC treatment.