Metabolic adaptations to crisantaspase treatment mediated by the pancreatic ductal adenocarcinoma

West Virginia University, Morgantown WV

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease without meaningful therapeutic options beyond the first salvage therapy. Targeting PDAC metabolism through amino acid restriction has emerged as a promising new strategy, with asparaginases, enzymes that deplete plasma glutamine and asparagine, reaching clinical trials. Although a Phase 2b clinical trial in metastatic PDAC patients demonstrated that Eryaspase (E. coli asparaginase encapsulated in erythrocytes) in combination with chemotherapy significantly prolonged progression free survival and overall survival, the confirmatory Phase 3 trial failed to meet the primary overall survival endpoint of overall. While amino acid restriction strategies are a promising therapeutic approach, metabolic support from the tumor microenvironment (TME) and the induction of compensatory metabolic pathways can limit its effectiveness. Pancreatic stellate cells (PSCs) are a key stromal component of the PDAC TME that have been shown to support PDAC growth in nutrient-poor conditions through the transfer of metabolites highlighting the importance of investigating crisantaspase in the context of PSC and PDAC interactions. Moreover, amino acid deprivation promotes activation of cytoprotective mechanisms, including the amino acid response (AAR) pathway and autophagy, which function to restore amino acid homeostasis. We recently reported that Erwinia chrysanthemi-derived asparaginase (called crisantaspase) induced tumor expression of asparagine and serine biosynthetic enzymes in murine PDAC models. We hypothesize that crisantaspase- mediated induction of autophagy and AAR signaling in both PDAC and PSCs promotes PDAC resistance to crisantaspase and that targeting these support pathways can restore crisantaspase sensitivity. To test this hypothesis, we propose to establish the effect of clinically available short-acting crisantaspase on the metabolic crosstalk between PDAC and PSCs and how autophagy and AAR response pathway induction in both cell types contributes to crisantaspase sensitivity. Furthermore, we will investigate pharmacological targeting of autophagy and the AAR pathway to enhance the anti-cancer effects of crisantaspase. Finally, to better recapitulate real-world PDAC/PSC interactions, we will establish paired primary cultures of human PDAC and PSCs derived from surgically excised tumors. Completion of the proposed studies will elucidate the mechanisms that PDAC cells can use to overcome crisantaspase treatment and identify novel targets to improve therapeutic response.