Download Pharmacogenomics and personalized medicines

Pharmacogenomics and
personalized medicines
Jean-Marie Boeynaems
[email protected]
OUTLINE
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Definitions : SNP, omics
Personalized choice of the medicinal product
Personalized dosage of the medicinal product
Problems and first achievements
Individualized treatment of cancer
Genome-wide association studies
Technological evolution of sequencing :
« The 1,000 $ genome challenge »
Generalization of genome sequencing :
ethical, legal and practical issues
A representative sample of the
slides that will be presented and
discussed during the course is
displayed hereafter.
Different types of SNP
• Outside genes : no impact
• In the genes coding sequence :
• change of base but not of amino acid (cf
redundancy of genetic code : GCA et GCC both
code for alanine)
• change of amino acid : more or less impressive
modification of function (loss or gain)
• In the promoter region :  or  transcription of the gene
and protein expression
• In the mRNA 3’-untranslated region :  (or ) sensitivity
to miRNA (that inhibit translation and destabilize mRNA).
Ome, Omics
• Genomics: all the genes
• pharmacogenomics : choice of personalized
medicine
• nutrigenomics : choice of best diet
• toxicogenomics : prediction of toxicity
• Epigenomics: all epigenetic changes in genome
• Transcriptomics: all the mRNAs  microarrays
• Proteomics : all the proteins
• Interactomics : all interactions between all proteins
• Metabolomics (or metabonomics) : all metabolites
• …
« Personalized medicines »
based on pharmacogenomics
• Identification of genes conferring to individuals who carry
them a better sensitivity to the therapeutic action of a
medicine or a better tolerance (drug metabolizing enzymes,
disease susceptibility factors)
• Genotyping before inclusion in a clinical trial statistical
power and cost
• Simultaneous marketing of a medicinal product and
availability of a genetic test to identify patients to treat
• Restriction of the market but higher price since efficacy is
optimized (or adverse effects decreased) .
From personalized medicine
to precision medicine
• Some are skeptical that medicine will really be
personalized, while others say that physicians have
always adapted treatment to their individual patients.
• Precision medicine implies that diseases are defined by
underlying molecular mechanisms rather than traditional
signs and symptoms.
Lancet 378 : 1678, 2011
Toward precision medicine
US National Research Council, nov 2011
Cancer Pharmacogenomics and Tumor
and Germline Genomes
Wang L et al. N Engl J Med 2011;364:1144-1153.
Anticancer drugs
approved by the Food
and Drug Administration
with labeling regarding
pharmacogenomic
biomarkers
Wang L et al. N Engl J Med 2011;364:1144-1153.
Lebrikizumab
treatment
in asthma :
efficacy
related to
serum periostin
Lebrikizumab is a monoclonal
antibody that neutralizes IL-13.
IL-13 induces bronchial epithelial cells
to secrete periostin.
Patients with high serum periostin
respond better.
Corren et al NEJM 2011
DNA cleaved in fragments
Fragments fixed on beads
(excess)
PCR amplification in emulsion
(1 bead/droplet)
Transfer to multi-well (pL) slide
(1 bead/well)
Addition of smaller beads covered
with enzymes involved in
sequencing
Elongation of fragments
Sequential injection of nucleotides
If the nucleotide is incorporated,
generation of light detected by a
camera
Cost of genome sequencing
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Genome of C Venter : 100x106 $
Genome of J Watson : < 1.5x106 $
X Prize Foundation challenge : 10,000 $
Race for $ 1,000 genome : 1,000 $
Complete Genomics in 2009 : 4,400 $
Cost of the detection of a single mutation by
Belgian genetics laboratories : 300 
Report freely accessible
on www.deloitte.com
Take home messages
• The business model of biopharma is changing and can
now include personalized medicines.
• The major difficulty is to identify SNPs with a strong
impact on treatment choice/dosage.
• Personalized medicines are making progress especially
in cancer treatment, but also in asthma.
• A key element is the astounding evolution of technology
with a dramatic decrease in the cost of sequencing.