LECTURE 8

• What can cause differences in how individuals respond to a drug?

  Variability in drug response
• What is the definition of pharmacogenomics?

  The study of genetic basis for the differences between individuals in responses to drugs
• What are the two main types of variability in drug response?

  • Variability in drug concentration at the site of action (Pharmacokinetic variation)
  • Absorption
  • Distribution
  • Metabolism
  • Excretion
  • Variability in individual response to the drug (Pharmacodynamic variation)
  • Differences in expression of drug targets
• What can cause variability in drug response?

  Many factors including genetic and environmental influences

  
• What are the two types of mutations discussed in pharmacogenomics?

  • Germline mutations
  • Happen in every cell in the body
  • Hereditary
  • ~10% of cancer
  • Somatic mutations
  • Characteristic for tumor cells
  • Nonheritable
  • 90-95% of cancer

  
• What are polymorphisms in genetics?

  Changes to gene sequence
• What is the most common type of genetic variation?

  Single nucleotide polymorphisms (SNPs)
• How do polymorphisms affect drug response?

  They can influence absorption, distribution, metabolism, and excretion of drugs
• What role do genetic variations in drug targets play?

  • Facilitate or impede drug binding
  • Affect the overall response to the drug
  • Example: G-protein-coupled receptors (GPCRs)
• What is personalized medicine in the context of pharmacogenomics?

  Individuals' DNA affects their response to drugs
• How is pharmacogenetics used in oncology?

  • Investigate the relationship between genetic polymorphism and drug-related toxicity
  • Develop targeted treatments
  • Improve survival rates for chemotherapeutic treatment
• What is 6-Mercaptopurine (6-MP) used to treat?

  Leukemia
• What causes interindividual toxicity in 6-MP treatment?

  Genetic polymorphism of 6-MP metabolizing enzymes
• Which enzyme primarily metabolizes 6-MP?

  Thiopurine S-methyltransferase (TPMT)
• What are the three major phenotypic subgroups of TPMT activity?

  • 90%: 2 functional alleles (normal activity) – H/H
  • 10%: Heterozygous (intermediate activity) – L/H
  • 0.3-0.5%: 2 non-functional alleles (little to no activity) – L/L

  
• What is the risk associated with L/H TPMT activity phenotype?

  Higher risk of toxicity due to accumulation of thioguanine nucleotides
• What happens to individuals with L/L TPMT activity phenotype?

  They accumulate excessive thioguanine nucleotides and are predisposed to severe toxicity reactions
• What are BRCA1 and BRCA2 associated with?

  • Risk of developing breast cancer
  • Tumor suppressor genes that repair DNA breaks
  • Germline hereditary mutations
  • 5-10% of breast cancer cases attributed to these genes
• What is the role of PARP inhibitors in cancer treatment?

  They are lethal for BRCA-deficient cells by promoting DNA break progression

  
• What is the function of the BRAF gene?

  It encodes a Raf serine-threonine kinase involved in growth signaling
• What is Vemurafenib used for?

  It is a B-Raf inhibitor that targets tumors carrying the V600E B-Raf mutation
• What type of cancer is Iressa™ (gefitinib) used to treat?

  Non-small cell lung cancer (NSCLC)
• What did Phase II studies show about Iressa™?

  They showed positive anti-tumor activity
• What was the outcome of Phase III studies for Iressa™?

  They failed to show a statistically significant survival benefit over standard of care
• What factor was the strongest predictor of a favorable outcome for Iressa™ treatment?

  The presence of EGFR mutation
• Why is studying variability in drug response important?

  • Few genes and/or environmental factors contribute a large risk
  • Many genes and/or environmental factors contribute a small risk
  • Understanding variability can lead to better personalized treatments