Discovery of drug-sensitizing genotypes in human cancer cells.

Clinical responses to anticancer therapeutics are often restricted to a subset of cases. Accumulating evidence indicates that response often correlates with a specific tumour genotype. Therefore, response rates could be substantially improved by directing treatment towards genetically-defined subsets of patients most likely to benefit. Toward this goal, we propose a scientific strategic alliance between investigators at Massachusetts General Hospital (MGH) and the Wellcome Trust Sanger Institute (WTSI) to "personalise" cancer therapy by identifying in vitro, prior to clinical trial, tumour cell genotypes that predict sensitivity to anticancer agents. We aim to expose approximately 1,000 cell lines derived from a broad spectrum of cancer classes to several hundred known and potential anticancer therapeutic agents correlating responses with genomic copy number information, cancer gene mutation data and expression data. Correlations between genotype or expression and response will then be validated in clinical specimens and will subsequently inform the design of clinical studies in which patients are stratified on the basis of a tumour genotype prior to treatment. The collaboration will develop and share the experience in automated high throughput exposure of cancer cell lines to small molecules at MGH and the background in large scale genotyping, sequencing and informatics at WTSI.