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.

Background: Medulloblastoma (MB) is the most common pediatric brain tumor. MB cells commonly escape from the primary tumor, spread to the surface of the brain and in the spinal cord where they grow and form metastatic tumors, which cause patient death. Although we know a lot about primary MB, little is known about the mechanisms of metastasis. Currently, there are no effective therapies to inhibit MB metastasis; therefore, their molecular analysis is needed to develop new effective therapies.

Background: Acute myeloid leukemia (AML) is one of the most challenging childhood cancers to treat. Induction chemotherapy remains the standard of care, but the incidence of refractory and relapsed AML is high. It remains unclear how certain AML cells manage to survive the extreme stress of chemotherapy. The search for specific genetic mutations that lead to therapy resistance has thus far not been successful. While mutations may certainly play a role, cells have other systems to protect them from stress, such as shifting metabolic programs. 

Background: Acute myeloid leukemia (AML) is one of the deadliest pediatric cancers, responsible for 10% of total cancer mortality in children. AML is caused by mutations in normal bone marrow stem cells that make them grow out of control (i.e. become malignant). There are many AML-causing mutations and they result in many different subtypes of AML with very different responsiveness to treatment and outcomes. We need a better mechanistic understanding of both common and divergent (i.e. subtype-specific) pathways leading to AML. 

Background: Pediatric myelodysplastic syndrome (MDS) is a disorder that causes low blood counts because specialized cells within the bone marrow, or the 'blood factory of the body', do not mature correctly. When this happens the cells cannot perform their intended job sufficiently. Currently, the only option for a cure for most children with pediatric MDS is a bone marrow transplant. Transplant is a difficult therapy with a less-than-ideal overall prognosis.