Deciphering the mechanisms underlying ASNase-associated pancreatitis (AAP)

Abstract

Pancreatitis is a life-threatening inflammatory disorder of the pancreas, and drug-induced pancreatitis is an important iatrogenic contributor to the problem. The drug asparaginase (ASNase) is a cornerstone therapy for leukemia, but about 10% of patients taking the cancer drug develop the complication of pancreatitis. Furthermore, discontinuation of ASNase due to pancreatitis leads to a suboptimal duration of ASNase treatment, and this shortfall tends to jeopardize event-free survival from leukemia. Thus, the goal of our proposed work is to address the major unmet need of deciphering the mechanisms underlying ASNase- associated pancreatitis (AAP). This is in order to come up with strategies that will predict who is at high risk for developing pancreatitis and, more importantly, to devise rescue therapies that will subvert the problem altogether. We hypothesized that patients who succumb to AAP have baseline metabolic alterations that predispose them to the development of pancreatitis. The specific aims of the proposal are thus to examine whether patients who succumb to AAP manifest at baseline (i.e. before receiving ASNase) metabolomic changes in comparison to matched control patients at baseline who did not develop pancreatitis with ASNase. In the current study, we will present preliminary findings from a metabolomic profile we performed from a case-control group of AAP and non-AAP patient plasma samples. The significance of the findings is that they will offer novel insight into devising rational diagnostic tools and rescue therapies to prevent the problem of AAP. On a broader level, the work will provide a framework to harness pharmaco-metabolomics, using AAP as a prime example, for designing personalized approaches to optimal drug selection and patient care.