NUDT15 Polymorphisms and Individualization of Thiopurine Therapy in Children with Acute Lymphoblastic Leukemia
Project Goal: The major goal of this proposal is to develop pharmacogenetically-guided mercaptopurine (MP) dosing algorithm to optimize thiopurine therapy in children with acute lymphoblastic leukemia (ALL). I hypothesize that we can rationally adjust thiopurine dosage according to variants in the NUDT15 gene and tailor their exposure to thiopurine active metabolites to the most efficient levels regardless of genotypes, similar to the principle of thiopurine S-methyltransferase-guided (TPMT) dose modification. I am confident that this research plan is an indispensable step to develop a genotype-guided MP dosing algorithm and eventually improves treatment outcome of pediatric ALL.
Project Update 2022: This project aims to translate the NUDT15 gene into genotype-based thiopurine dosing algorithm. With the funding from the Alex’s Lemonade Stand Foundation, we have comprehensively characterized toxicity related NUDT15 variants based on which we could improve the ability to implement genotype-guided thiopurine therapy to mitigate toxicity. In a mouse model of NUDT15-mediated thiopurine toxicity, we have defined a potential metabolite marker to predict thiopurine toxicity, based on which thiopurine dosage can be rationally individualized on the basis of NUDT15 genotypes. Based on these compelling data, we further establish translational data for clinical implementation of NUDT15-genotype guided thiopurine dosing individualization in children with ALL.
