Genetic Polymorphisms Affecting Chemotherapy Disposition

Project: Research project

Description

DESCRIPTION (provided by applicant): Cancer treatment is complicated by inter-individual variations in responses and toxicities. Genetic polymorphisms in the enzymes and transporters responsible for the disposition of these drugs may contribute to the observed variability. Due to the narrow therapeutic window of these agents, pharmacogenetic screening prior to anticancer drug administration may lead to identification of specific populations predisposed to drug toxicity or poor drug response. One hope of pre-treatment genotyping would be to eventually allow for those patients who are at risk for drug toxicities or therapeutic failure to be identified and treated appropriately. Genetic heterogeneity in drug metabolizing and target enzymes has been demonstrated to affect the inter-individual variability in the pharmacokineties (PK) and toxicities of several drugs such as 5-FU, 6-MP, amonafide and CPT-11. Besides enzymes, genetic variability in the ATP-dependent effhLx pumps, MDR1 (PGP) and MRP2 (cMOAT), has been demonstrated and results in alterations in drug disposition. Interestingly many of these allelic variations correlate with ethnicity and there are striking differences in the allelic frequencies of many of these genes between Caucasians and African-Americans. Due to a longstanding interest in clinical pharmacology and differential drug toxicity and response, it is my career goal to be a clinical translational researcher with the skills to bridge advances in pharmacogenetics with clinical trial design, and ultimately formulate studies that lead to dose optimization and in some cases treatment selection for individual patients. In this proposal I delineate a unique training plan with appropriate mentorship in clinical research by Mace Rothenberg, MD and mentorship in basic science research by Richard Kim, MD, where basic laboratory techniques and discoveries in the area of pharmacogenomics can be applied in well-designed, hypothesis-driven clinical trials. A plan for didactic training in pharmacogenetic techniques is included to provide a strong foundation for a career in translational research. Two translational research projects are proposed to correlate genetic polymorphisms in enzymes, transporters and nuclear receptors with clinical pharmacokinetic and toxicity data from a cohort of cancer patients treated with chemotherapeutic agents that are dependent upon the activity of these drug disposition determinants. Because a number of these enzyme and transporter pathways have marked variability that correlate with ethnicity, these projects will focus on enrolling Caucasian and African-American patients to effectively address these concerns. Enrollment to these studies will be facilitated by the unique cooperative agreement between the Vanderbilt-Ingram Cancer Center and Meharry Medical College. This grant will allow the protected time to pursue the appropriate training and the funds to support anticipated laboratory and tuition costs. In completing the proposed training and projects, I will gain the necessary expertise in the design of clinical translational research studies and characterization of genetic variations in chemotherapeutic drug disposition to develop an independent career in patient-oriented research and compete effectively for future NIH support, through R01, R03 and R21 funding mechanisms.
StatusFinished
Effective start/end date5/1/044/30/10

Funding

  • National Institutes of Health: $124,038.00
  • National Institutes of Health: $124,038.00
  • National Institutes of Health: $124,038.00
  • National Institutes of Health: $124,038.00
  • National Institutes of Health: $122,585.00
  • National Institutes of Health: $1,453.00

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Genetic Polymorphisms
Drug Therapy
Drug-Related Side Effects and Adverse Reactions
Translational Medical Research
Pharmacogenetics
Pharmaceutical Preparations
Enzymes
Mentors
irinotecan
amonafide
African Americans
omega-Chloroacetophenone
Research
Clinical Trials
Therapeutics
Neoplasms
Genetic Heterogeneity
Clinical Pharmacology
Organized Financing
Financial Management