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A systems approach points to a therapeutic role for retinoids in asparaginase-associated pancreatitis

Cheng-Yu Tsai,Toshie Saito,M. Sarangdhar,M. Abu-El-Haija,Lihua Wen,Bomi Lee,Mang Yu,Den A. Lipata,M. Manohar,M. Barakat,K. Contrepois,T. Tran,Y. Théorêt,Nazarov Bo,Ying Ding,Kristen Stevenson,E. Ladas,L. Silverman,L. Quadro,T. Anthony,A. Jegga,S. Husain

Published 2023 in Science Translational Medicine

ABSTRACT

Among drug-induced adverse events, pancreatitis is life-threatening and results in substantial morbidity. A prototype example is the pancreatitis caused by asparaginase, a crucial drug used to treat acute lymphoblastic leukemia (ALL). Here, we used a systems approach to identify the factors affecting asparaginase-associated pancreatitis (AAP). Connectivity Map analysis of the transcriptomic data showed that asparaginase-induced gene signatures were potentially reversed by retinoids (vitamin A and its analogs). Analysis of a large electronic health record database (TriNetX) and the U.S. Federal Drug Administration Adverse Events Reporting System demonstrated a reduction in AAP risk with concomitant exposure to vitamin A. Furthermore, we performed a global metabolomic screening of plasma samples from 24 individuals with ALL who developed pancreatitis (cases) and 26 individuals with ALL who did not develop pancreatitis (controls), before and after a single exposure to asparaginase. Screening from this discovery cohort revealed that plasma carotenoids were lower in the cases than in controls. This finding was validated in a larger external cohort. A 30-day dietary recall showed that the cases received less dietary vitamin A than the controls did. In mice, asparaginase administration alone was sufficient to reduce circulating and hepatic retinol. Based on these data, we propose that circulating retinoids protect against pancreatic inflammation and that asparaginase reduces circulating retinoids. Moreover, we show that AAP is more likely to develop with reduced dietary vitamin A intake. The systems approach taken for AAP provides an impetus to examine the role of dietary vitamin A supplementation in preventing or treating AAP. Description The cancer drug asparaginase reduces circulating retinoids and predisposes patients with reduced dietary vitamin A intake to pancreatitis. Protecting the pancreas from asparaginase Asparaginase is a mainstay of acute lymphoblastic leukemia (ALL) treatment, but up to 10% of treated individuals develop the severe adverse event of acute pancreatitis. Tsai et al. report that individuals with ALL who developed pancreatitis are more likely to have lower plasma carotenoids; experiments in mice showed that asparaginase treatment itself was enough to lower retinol concentrations. An analysis of patient electronic health records indicated that greater vitamin A intake during asparaginase treatment for ALL reduced the likelihood of developing drug-induced pancreatitis, suggesting that vitamin A supplementation during asparaginase treatment should be further investigated. —CAC

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