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Pharmacogenetics - Tumour-specific (Chronic Myeloid Leukaemia…
Pharmacogenetics - Tumour-specific
Cancer
tumours have specific DNA changes and drug response
ideal anti-cancer drugs act to kill all tumour cells to prevent relapse but act at tumour-specific targets to avoid toxicity by killing other high dividing tissue like gut/bone marrow
new drugs in development are small molecules/monoclonal Ab with predicted response based on tumour profile
Breast Cancer (HER2/Herceptin)
Breast Cancer
most common female cancer EU/US
1 in 10 females will get malignant breast tumour
300 male cases per year UK
HER2
Human epidermal growth factor receptor 2 - receptor tyrosine kinase
dimerisation leads to cascade and proliferation
overexpressed in 25% of breast cancers
due to txn upregulation or amplification in copies/activity
key biomarker (FISH - fluroescent insitu hybridisation HER2 against chr 17 centromere)
Herceptin
mAb against HER2
blocks dimerisation/subsequent cascade and allows Ab-mediated cytotoxicity
also sensitises cells to more standard cytotoxic drugs
increases disease free survival at 4yrs from 67 to 85%
HER2+ responsive to herceptin treatment
Chronic Myeloid Leukaemia
750 cases UK/year
age 55+
more WBC with irregular nuclei and undifferentiated bm cells
used to be survival of 3-4yr
Philadelphia Chromosome
in 95% of patients t(9;22)(q34;q11)
translocation produced fusion bcr-abl gene on Chr22
abl tyrosine kinase involved in cell regulation (tightly controlled)
fusion protein loses regulatory N-terminal SH3 domain and becomes constitutively active
leads to more proliferation, less death and altered adhesion - tumourigenesis
Imatinib
small molecule inhibitor of abl kinase ATP binding site
compared to standard combination therapy - more cytogenetic response, better tolerated, improved QoL, >80% 8 yr survival
expensive but huge impact, now considering for solid tumours
GWAS - Statin-Induced Myopathy
GWAS
unbiased genome scan
cheaper and easier than pedigrees
increases stat power detects alleles of small effect
Statin-induced myopathy
GWAS of myopathy vs not on 80mg simvastatin daily
non-synonymous SNP in SLCO1B1 attributed to >60% of myopathy cases
then replicated in 20,000
85 vs 90
encodes OATP1B1 regulating hepatic stain uptake