Abstract IA06: Genomic approaches to drug discovery

Abstract

Abstract The principles of genomics (systematic, high throughput approaches to biology) can increasingly be brought to bear on drug discovery. Our group is developing two new approaches: Connectivity Map and PRISM. The concept of the Connectivity Map (CMap) is that disease states, cellular states and the action of pharmacologic or genetic perturbation can be captured by gene expression profiling. In order to make large-scale perturbational profiling feasible, we developed a high-throughput, ultra-low cost profiling method (named L1000) whereby the abundance of 1000 transcripts are quantified by hybridization to Luminex microspheres. As part of the NIH LINCS program, we have now generated over 2 million such L1000 profiles representing knock-down and over-expression of over 3000 genes and perturbation with over 4000 small molecules in more than 15 cell types. Examples of discoveries emanating from this next generation Connectivity Map will be presented. The PRISM method takes inspiration from recent large-scale drug sensitivity profiling studies demonstrating the value of determining the pattern of compound killing across a large panel of genetically characterized cancer cell lines. In order to increase the scale at which such studies can be performed, we inserted unique molecular barcodes (24-mer oligonucleotides) into the genomes of cancer cell lines, such that the lines could then be pooled and the pooled lines exposed to a compound of interest. Drug sensitivity is then quantified by changes in abundance of the molecular barcodes. We have demonstrated feasibility of pooling more than 500 cancer cell lines in a single pool, and have demonstrated feasibility of high throughput screening using the PRISM method. These experiments suggest that PRISM can be used as a starting point for oncology drug discovery and for the characterization of lead compounds for the genotype-specific patterns of cancer cell killing. Examples of recent PRISM discoveries will be presented. Citation Format: Todd R. Golub. Genomic approaches to drug discovery. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr IA06.