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Evans Lab: Research

Our lab focuses on the pharmacogenomics of acute lymphoblastic leukemia (ALL), with an overarching goal of identifying genomic determinants of treatment response and translating those findings to improve cure rates and reduce toxicity of therapy. Childhood ALL, the most common pediatric cancer, is now curable in approximately 90% of children (Pui and Evans, N Engl J Med, 2006). The primary cause of disease relapse is resistance to one or more of the medications used to treat ALL, often for reasons that remain unclear. Furthermore, as cure rates continue to improve, there is increasing importance in reducing acute and chronic toxicities of therapy, to improve quality of life of patients during and after treatment. There is growing evidence that genome variation among patients contributes to both drug resistance and toxicity of antileukemic agents, and elucidation of these pharmacogenomic determinants of treatment response holds promise to improve the “precision medicine” paradigm for childhood ALL.

Our aim is to identify genes and genome variants that contribute to drug resistance or drug toxicity, including the influence of germline variants, such as single nucleotide polymorphisms (SNPs) and somatic variants including DNA methylation, copy number alterations, mRNA expression, miRNA expression  and single nucleotide variants (SNVs). The lab also selectively undertakes research to elucidate mechanisms by which these genome variants alter drug effects.

Previous research from our lab identified inherited variants (SNPs) in the gene encoding thiopurine methyltransferase (TPMT) and their contribution to the toxicity of mercaptopurine, a drug used in curative therapy of childhood ALL (Krynetski et al., Am J Hum Genet, 1996; Marshall et al., Science, 2003). Based on these findings, patients with ALL at St. Jude now receive mercaptopurine treatment that is individualized based on their inherited TPMT genotype/phenotype (see , Evans and Relling, Science 1999; Nature, 2004; Relling et al., Clin Pharmacol Ther, 2013), resulting in lower toxicity without compromising efficacy of treatment. Subsequent collaborations with the labs of Drs. Jun Yang and Mary Relling, identified inherited variants in NUDT15 that also predispose to mercaptopurine cytotoxicity through loss of function of the NUDT15 enzyme that normally dephosporylates the active thioguanine neucleotides (Yan et al, JCO 2015; Moriyama et al, Nature Genetics 2016). Genetic variants in both TPMT and NUDT15 are now used to guide the selection of mercaptopurine doses in the current frontline clinical trial for ALL at SJCRH (i.e., Total XVII).

Building on this paradigm, we are now focused on research to identify the genetic or epigenetic bases for resistance to or toxicity from other commonly used antileukemic agents. This has revealed an inherited variant in CEP72 that is associated with an increased incidence and severity of vincristine-induced neuropathy in ALL patients (Diouf et al, JAMA 2015), with studies in iPSC neurons documenting that low expression of CEP72 enhances sensitivity of neurons to vincristine, which was also evident when CEP72 expression was reduced in ALL cells. Our research on mechanisms of de novo resistance of primary ALL cells has identified a novel mechanism of glucocorticoid resistance in ALL, involving over-expression of caspase 1 and its activator NLRP3, leading to cleavage of the glucocorticoid receptor in ALL cells (Paugh et al, Nature Genetics 2015). Similar studies of de novo resistance to cytotoxic and targeted antileukemic agents are currently underway as part of the NIH-funded Center for Precision Medicine in Leukemia at St. Jude.

Our long-term goal is to translate these pharmacogenomic findings into more effective and less toxic treatment of ALL in children and adults (see Relling and Evans, Nature, 2015).