The goal of this mentored career development award application is to consolidate my diverse training experiences in laboratory and clinical pharmacology, human genetics, and clinical investigation into a focused research program in "Genome-wide molecular epidemiology of treatment outcome and cancer risk". The purpose of this program will be to discover and test the biological function of novel germline genetic variation that might serve as markers of 1) severe toxicity and survival in cancer patients treated with chemotherapy, and 2) cancer susceptibility. These markers will be identified through genome-wide (GW) association studies (GWAS), and my previous training and research experience do not pertain to GW investigations. To undertake research that combines GW data with molecular, genetic, epidemiology and bioinformatics techniques, I will be required to apply these technologies to genomic population data. This program will be constructed through a series of clinical, epidemiology, and laboratory studies. I propose to use unbiased genomic approaches for the discovery of novel candidate genes as markers of outcome of chemotherapy. The same approaches will be also applied to identify novel candidates of cancer susceptibility by benefiting from publicly available resources of GW information from control individuals without cancer. Enrichment of the information generated from the GW data will be derived from additional genotyping and/or resequencing of genomic regions that showed significant associations in the GWAS. It is very likely that the significant single nucleotide polymorphisms (SNPs) in the GWAS will not have an established molecular function, and several strategies will be used to support the observed clinical associations. The proposed research plan and subsequent investigations will substantially increase the understanding of the pleiotropic effects of heritable genetic information in humans. This work will provide a knowledge framework for designing controlled replication studies of treatment outcome and cancer risk using highly selected informative markers. These applications could inform interventions designed to establish the risk-benefit ratio of cancer chemotherapy and to reduce the prevalence of cancer in the population.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Academic/Teacher Award (ATA) (K07)
Project #
5K07CA140390-05
Application #
8320340
Study Section
Subcommittee G - Education (NCI)
Program Officer
Perkins, Susan N
Project Start
2009-09-23
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
5
Fiscal Year
2012
Total Cost
$130,502
Indirect Cost
$9,667
Name
University of North Carolina Chapel Hill
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Innocenti, Federico; Schilsky, Richard L; Ramírez, Jacqueline et al. (2014) Dose-finding and pharmacokinetic study to optimize the dosing of irinotecan according to the UGT1A1 genotype of patients with cancer. J Clin Oncol 32:2328-34
Van Loon, Katherine; Owzar, Kouros; Jiang, Chen et al. (2014) 25-Hydroxyvitamin D levels and survival in advanced pancreatic cancer: findings from CALGB 80303 (Alliance). J Natl Cancer Inst 106:
Gillis, N K; Patel, J N; Innocenti, F (2014) Clinical implementation of germ line cancer pharmacogenetic variants during the next-generation sequencing era. Clin Pharmacol Ther 95:269-80
Fortina, Paolo; Al Khaja, Najib; Al Ali, Mahmoud Taleb et al. (2014) Genomics into Healthcare: the 5th Pan Arab Human Genetics Conference and 2013 Golden Helix Symposium. Hum Mutat 35:637-40
Pare-Brunet, Laia; Glubb, Dylan; Evans, Patrick et al. (2014) Discovery and functional assessment of gene variants in the vascular endothelial growth factor pathway. Hum Mutat 35:227-35
Patel, Jai N; McLeod, Howard L; Innocenti, Federico (2013) Implications of genome-wide association studies in cancer therapeutics. Br J Clin Pharmacol 76:370-80
Glubb, Dylan M; Paugh, Steven W; van Schaik, Ron H N et al. (2013) A guide to the current Web-based resources in pharmacogenomics. Methods Mol Biol 1015:293-310
Innocenti, Federico; Ramirez, Jacqueline; Obel, Jennifer et al. (2013) Preclinical discovery of candidate genes to guide pharmacogenetics during phase I development: the example of the novel anticancer agent ABT-751. Pharmacogenet Genomics 23:374-81
Glubb, Dylan M; Innocenti, Federico (2013) Architecture of pharmacogenomic associations: structures with functional foundations or castles made of sand? Pharmacogenomics 14:1-4
Gamazon, Eric R; Innocenti, Federico; Wei, Rongrong et al. (2013) A genome-wide integrative study of microRNAs in human liver. BMC Genomics 14:395

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