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The Cancer Genome Project at the Wellcome Trust Sanger Institute (UK) and the Center for Molecular Therapeutics, Massachusetts General Hospital Cancer Center (USA) have recently entered into a unique 5-year collaboration to combine their respective expertise in cancer genomics and molecular therapeutics. The goal of this effort is to discover tumour biomarkers that define subsets of drug-sensitive cancer patients, and can thereby be used to inform the design of clinical trials of investigational compounds and the optimal clinical application of cancer drugs—i.e., “personalized cancer medicine”. The Center for Molecular Therapeutics is at the forefront of research into molecular therapeutics and has pioneered the use of high-throughput platforms for examining the relationship between tumour cell genomics and sensitivity to candidate anti-cancer agents. The Cancer Genome Project has led the way in the systematic analysis of cancer genomes to identify somatic mutations and hence identify genes critical in the development of human cancers. As part of this unique collaboration, we plan to screen >1000 genetically characterised human cancer cell lines with a wide range of anti-cancer therapeutics, and correlate sensitivity patterns with extensive genomic data, with the goal of identifying genomic determinants of anti-cancer drug response that will inform clinical trials and patient treatment. This large collection of cell lines enables us to capture much of the genomic heterogeneity that underlies human cancer, and which appears to play a critical role in determining the variable response to treatment with specific agents across the patient population.

Cancer cell lines are seeded on 96-well microplates at a density sufficient to ensure that they are in a log growth phase at the end of experiment. The cell line is drugged using an automated liquid handling platform with a concentration range (typically 9 concentrations) of each compound. The effect on cell viability is measured after 72 hours using either a red fluorescent nucleic acid stain (adherent lines) or resazurin (suspension lines).

The majority of cell lines screened have been extensively genetically characterized: - Affymetrix SNP 6.0 Array (906,600 SNPs, 946,000 copy number probes) - Affymetrix Human Genome U133A gene expression - Sequence analysis of 70 known cancer genes It is anticipated that additional levels of characterization will be added over the course of the project, including methylation status and whole exome sequencing.

Many of the compounds in the screen have been obtained from commercial organizations under an MTA and as such are commercially sensitive. Thus, many of the compounds have been anonymized with a unique ID number. The putative target(s) has been identified to enable researchers to search for compounds that target specific pathways or genes.