The AACR-FNAB Career Development Award for Translational Cancer Research is open to junior faculty in their first full-time faculty appointment. Research projects are restricted to translational cancer research focused on any individualized therapeutic area. Proposed project must have implications for individualized cancer treatment and must make use of human biopsies or samples, such as needle biopsies or circulating cancer cells. In vivo primary tumor explants meet these criteria, but xenografts from established cell lines do not.
Christine L. Phillips, M.D.
Instructor of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
Genetic Model of Cytarabine Sensitivity in Children with AML
"Approximately half of children with acute myeloid leukemia (AML) will become long-term survivors. Cytosine arabinoside, (cytarabine or Ara-C) is likely the most important drug in cure, and has been used in serial clinical trials to achieve the current successes. Despite this progress, a proportion of children still die of toxicity and a larger number will relapse. Understanding the basis for this inter-individual variation in response to therapy will help extend cure to these patients. We hypothesize that subtle genetic variations, or single nucleotide polymorphisms (SNPs), which influence sensitivity to cytarabine can predict outcome of therapy for childhood AML.
"We have selected two complementary approaches to identify genetic polymorphisms that modify response to cytarabine. We will use a candidate gene approach to identify relevant genetic polymorphic variants in genes that are known to play a role the metabolism of cytarabine. Secondly, we will use data from a genome-wide analysis of loci associated with cytarabine sensitivity to identify the novel loci that may modify clinical outcomes using cytarabine. Our collaborator, Dr. Eileen Dolan, has identified over 100 SNPs that are associated with cytarabine sensitivity using a pre-clinical International Hap Map lymphoblastoid cell line. These SNPs contribute to cytarabine-induced cytotoxicity, and will be evaluated to identify markers associated with therapeutic response in vivo. We will utilize DNA from a large cohort of 450 children with AML who participated in recent Children’s Oncology Group trials and consented for its use in further genetic research. The mature clinical data is available to identify associations between cytarabine metabolism SNPs, pharmacodynamic SNPs and treatment outcome. The combination of the two approaches allows for the development of a comprehensive model which explores both the pharmacokinetic and pharmacodynamics properties of the drug. To control for potential false discovery, we plan to replicate positive findings in an independent dataset, the successor study (AAML0531). Our goal is to develop a genetic model that accounts for inter-individual variation and allows us to individualize therapy. Knowledge of genetic characteristics that predict either excessive toxicity, or inadequate therapy (relapse) at the time of diagnosis will allow for selection of individualized cancer treatments and will improve survival. The AACR-FNAB Career Development Award for Translational Research will provide key support for me during this project and enable me to further advance towards an independent career in translational research in pediatric leukemia."
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