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

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

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. References
Lu, D.-Y., Lu, T.-R., Xu, B. & Ding, J. Pharmacogenetics of cancer therapy: breakthroughs from beyond? Futur. Sci. OA 1, fso (2015).
Pirmohamed, M. Pharmacogenetics and pharmacogenomics. Br. J. Clin. Pharmacol. 52, 345–347 (2001).
Patel, J. N. Cancer pharmacogenomics, challenges in implementation, and patient-focused perspectives. Pharmgenomics. Pers. Med. 9, 65–77 (2016).
Savonarola, A., Palmirotta, R., Guadagni, F. & Silvestris, F. Pharmacogenetics and pharmacogenomics: Role of mutational analysis in anti-cancer targeted therapy. Pharmacogenomics J. 12, 277–286 (2012).
Relling, M. V and Evans, W. E. Pharmacogenomics in the clinic. Nature 526, 343–350 (2015).
Low, S.K., Takahashi, A., Mushiroda, T. & Kubo, M. Genome-Wide Association Study: A Useful Tool to Identify Common Genetic Variants Associated with Drug Toxicity and Efficacy in Cancer Pharmacogenomics. Clin. Cancer Res. 20, 2541–2552 (2014).
Dickmann, L. J. & Ware, J. A. Pharmacogenomics in the age of personalized medicine. Drug Discov. Today Technol. 21– 22, 11–16 (2016).
Becquemont, L. HLA: a pharmacogenomics success story. Pharmacogenomics 11, 277–81 (2010).
Wang, D., Papp, A. C. & Sun, X. Functional characterization of CYP2D6 enhancer polymorphisms. Hum. Mol. Genet. 24, 1556–1562 (2015).

13. Thank you for your attention!