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Pharmacogenomics. The study of the role of inheritance in individual variation in drug response phenotypes.A major component of
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1. Cancer Pharmacogenomics From Bench to Bedside Liewei Wang M.D.,PhD.
Assistant Professor
Department or Molecular Pharmacology & Experimental Therapeutics
Mayo Clinic Rochester
2. Pharmacogenomics The study of the role of inheritance in individual variation in drug response phenotypes.
A major component of “Personalized Medicine”.
3. Clinical Goals
Avoid adverse drug reactions
Maximize drug efficacy
Select responsive patients Pharmacogenomics
4. Scientific Goals
Link variation in genotype to variation in phenotype
Determine mechanisms responsible for that link
Translate the link into enhanced understanding, treatment and prevention of disease
Pharmacogenomics
6. Classical pharmacogenomic examples FDA Hearings
Pharmacogenetics and Drug Labeling
Thiopurines – TPMT
Irinotecan – UGT1A1
Warfarin – CYP2C9 and VKORC1
Tamoxifen – CYP2D6
8. Genome-wide association study Clinical GWAS
GWAS using model systems (hypothesis generating and hypothesis testing)
9. Human Variation Panel cell lineA model system Publically available, widely used for genetic studies
Ethnic diversity (100 CA, 100 AA and 100 HCA)
Represent common genetic variation among individuals
A good model system for pharmacogenomic studies
10. Genome-wide SNP data
1.3 million SNPs/cell line
Expression array data
54,000 probe sets/cell line
MicroRNA
800 probe sets/cell line
2,000,000 genomic data points/cell line
576,000,000 genomic data points total for 288 cell lines
15. Potential clinical implication Two genes were identified to be significantly associated with response to gemcitabine and AraC (NT5C3 and FKBP5) (Li et.al. Cancer Research 2008; 68: (17). Sept. 1, 2008; Cancer Cell, in press)
These genes can be potentially used as biomarkers for prediction of patients who might respond better to theses treatments.
17. Pharmacogenomics Ethical Challenges
Confidentiality
Insurance
Therapeutic “activism”