BCH3031 Lecture Notes - Lecture 22: The Cancer Genome Atlas, Drug Design, Receptor Tyrosine Kinase
25 May 2018
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Lecture 22 – Using Genomic Information in Drug Development: Targeting the
protein through rational drug design, antibody development or library screening
Mapping the Cancer Genome
• More than 1,500 Americans die from cancer every day
• Cancer Genetic Markers of Susceptibility (CGEMS)
o Project was launched in 2005
o Conduct whole-genome association studies to identify genes that
confer susceptibility to prostate and breast cancer
o Capitalizes on new knowledge of single nucleotide polymorphisms
(SNPs) in human genetic variation
o SNP selection strategy process: recruit of people → whole genome
scan → quality controls → discovery of SNPs (3 year period)
o Outcome for Breast Cancer
▪ Conducted by genotyping 528, 173 SNPs in 1,145
postmenopausal women of European ancestry with invasive
breast cancer and 1,142 controls
▪ Four SNPs in intron 2 of FGFR2 (encodes receptor tyrosine
kinase and is overexpressed in breast cancers)
• The Cancer Genome Atlas (TCGA)
o Aims to identify genetic alterations in human cancer
o Complete genome sequencing → put information in database for all
scientists to study
o Profiling 20 tumour types (brain, lung, ovarian) by analysing the
expression profiles and genomic changes associated with each cancer
sample
Two Examples of Potential Drug Targets in Cancer (proteins that are overexpressed
in cancer)
1. SIM2 in colon cancer
2. ErbB2 in breast cancer
Questions are:
• Is the molecule suitable as a drug target?
• If it is, can an effective drug be developed with high affinity and specificity?
How are Drugs Developed?
• Discovery of gene sequence that encodes drug target → protein sequence →
can work out protein 3D structure → through screening work out protein
inhibitor discovery → drug development (therapeutic)
o Specific inhibitor may represent treatment for that disease
o Through screening chemical libraries, antibody production or via
knowledge of protein’s 3D structure
• Screening chemical libraries (1)
o Drug target is screened against a selection of chemicals that possess a
wide range of chemical functionalities
o May be derived from natural products or synthesised by chemists
o Effective assay is required that can detect drug-target interactions or
detect drug target inhibition
o Small molecules can be readily and cheaply synthesised (stable when
ingested – can readily fuse through membrane)
• Monoclonal antibody drugs (2)
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