Beatriz Pérez González 2017/18 Genomics Pharmacogenomics Beatriz Pérez González 2017/18 Genomics

Content Introduction Clinical applications Pharmacogenomics and cancer The role in cancer treatment Challenges and conclusions

There can be alterations in the drug’s… Introduction Pharmacogenetics Pharmacogenomics One gene Whole genome vs. ‘One dose fits all’ vs. personalised medicine Drug prescription can be adapted to maximize efficacy and minimize toxicity Increased number of targeted therapies are receiving accelerated drug approval Pharmacokinetics Pharmacodynamics There can be alterations in the drug’s… or ADME Target or pathway

Clinical applications Abacavir hypersensitivity Inhibitor of reverse transcriptase HLA-B*5701 allele Treatment HIV Exclude carriers of this allele 5-8% cases of severe hypersensitivity Disappearance of the hypersensitivity syndrome caused by abacavir

Clinical applications CYP2D6 Metabolizes nearly 25% of used drugs and it has a large inter-individual variability Most important pharmacogenetic biomarker Different variants affect more than 41 drugs’ response CYP2D6 genotype has robust effects on metabolizer phenotype tricyclic antidepressants Codeine intermediate poor ultra-rapid extensive

Pharmacogenomics and cancer Mutations patient’s DNA (inherited) Mutations tumor DNA (acquired) Predicting pharmacokinetics Predicting pharmacodynamics Biomarker: Characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic ones or pharmacological response. Prognostic biomarker Predictive biomarker HER2 Provides information on the likely course of cancer without the treatment Detect those patients most likely to benefit from a treatment or predisposed to toxicity

Crizotinib targets the ALK protein inhibiting its activity ALK in NSCLC 5% cases: Anaplastic lymphoma kinase (ALK) suffers an abnormal fusion with EML4  constitutively activation Crizotinib targets the ALK protein inhibiting its activity Acquire resistance  Ceritinib. Savonarola, A et al. Pharmacogenomics J. 2012

NSCLC patients with ALK mutations cannot benefit from EGFR mutations EGFR in NSCLC EGFR activating mutations Gefitinib or Erlotinib Acquire resistance  Afatinib NSCLC patients with ALK mutations cannot benefit from EGFR mutations Savonarola, A et al. Pharmacogenomics J. 2012

BRAF in melanoma Approx. 50% of melanoma cases carry mutations in BRAF 90%: Glutamic acid substitution for valine at codon 600 V600E Promoting cell proliferation and tumor growth Vemurafenib

UGT1A1*28 allele related to reduced expression and activity UGT1A1 and Irinotecan Irinotecan is a topoisomerase I inhibitor, prodrug used for metastatic colorectal cancer. Irinotecan SN-38 (active) Metabolism SN-38G Inactivation Inactivated by uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) UGT1A1*28 allele related to reduced expression and activity Severe toxicity It is also an example of the potential under-dosing of the homozygous or heterozygous patients for the WT allele

Conclusions Increased targeted therapies mean greater reliance on biomarkers to help decide the most beneficial treatment for a patient. Sometimes the number of patients in studies to identify genetic markers is not enough. GWAS is a promising method to identify novel common genetic variations in pharmacogenomics. Cost-effectiveness analysis are difficult to determine. “With the continuing decline in cost of sequencing, in a not-too-distant future, every individual will have their entire inherited genome sequenced early in life for clinical purposes” Relling, M. V et al. Nature. 2015

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