Pharmacogenomic factors associated with severe acute toxicities and survival in pediatric Latino patients with acute lymphoblastic leukemia

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1 PROJECT SUMMARY/ABSTRACT 2 Research Project: Latino children have the highest risk of developing acute lymphoblastic leukemia (ALL), a 3 higher cumulative incidence of relapse, and lower survival rates. We hypothesize that Latino children with ALL 4 will exhibit more severe acute toxicities and a unique pattern of drug toxicity clusters. We also believe that these 5 toxicities and clusters are more prevalent in Latino patients, are related to pharmacogenomic factors and are 6 associated with an increased risk of relapse and reduced event-free survival. To demonstrate these points, we 7 will validate prior work with pegaspargase-related toxicity clusters, then apply this approach to describe toxicity 8 clusters for other agents used throughout ALL treatment. We will define the relationship between severe acute 9 toxicities and toxicity clusters on the risk of relapse and event-free survival and examine the pharmacogenomics 10 of toxicities and clusters using candidate and genome-wide association studies. Lastly, we will describe the 11 frequency of variant risk alleles from our cohorts by analyzing other pharmacogenomic datasets. 12 Candidate plan and goals: Dr. Bernhardt aspires to be a leading, independent, clinician-scientist in the field of 13 clinical pharmacogenomics. Her overarching goal is to improve the care of children with cancer by translating 14 genomic science to clinical decision-making at the bedside. This goal will be accomplished by developing 15 knowledge and research expertise in clinical pharmacogenomics. Dr. Bernhardt will participate in formal and 16 informal training relevant to her research, including didactic and hands-on experiences in pharmacogenomics, 17 translational biology, and epidemiology. She will be mentored by Drs. Michael Scheurer and Richard Gibbs, 18 renowned investigators in molecular epidemiology and human genetics (respectfully). Dr. Bernhardt’s advisory 19 committee will guide her research and career development during formal meetings and one-on-one interactions. 20 Baylor College of Medicine (BCM) has invested in Dr. Bernhardt’s career development by assuring 75% 21 protected time as described in this application, and commitment to her success in the long-term. 22 The Environment: Career development and research activities will be conducted at BCM and Texas Children's 23 Hospital (TCH). BCM is a premiere medical school and academic health science center, highly ranked in funding 24 from the National Institutes of Health and the National Science Foundation. BCM actively trains more than 3,000 25 medical, graduate, and health professions students and fellows. Texas Children’s Cancer and Hematology 26 Centers, a joint BCM/TCH program, is the largest pediatric cancer and hematology program in the United States. 27 Research and training opportunities will occur within the TXCH Epidemiology Program, BCM Human Genome 28 Sequencing Center, and TCH Molecular Pathology programs. Programs at BCM and TCH offer extensive 29 opportunities for mentored and self-directed training, didactic coursework, peer interactions, and ongoing 30 professional development across multiple scientific domains.