Abstract A102: NCI-60 response profiles of >400 investigational oncology agents: A resource enabling drug and biomarker discovery.

Abstract

Abstract We have acquired >400 investigational oncology agents, comprised primarily of targeted small molecules currently in clinical and/or preclinical anticancer studies. As oncology treatment moves toward personalized targeted therapeutic agents, the NCI-60 human tumor cell line panel is an ideal community-wide tool to further understanding of the disease targets of new agents. The panel includes cell lines from nine tumor types, and is extremely well characterized at the molecular level, with both in-house and crowd-sourced characterization, including exome sequence for mutations, SNPs, DNA methylation, metabolome, mRNA, microRNA, and protein expression. This molecular characterization dataset enables interrogation of patterns of growth inhibition by the investigational drug set looking for characteristics of the cell lines that determine sensitivity. More than 150,000 small molecules, including all (> 100) FDA-approved anticancer drugs and now our acquired set of 400 investigational oncology agents have been screened against the panel for their effects on cell growth. We have used a number of online tools to enable data analysis for this set, including COMPARE (http://dtp.nci.nih.gov/compare/), which provided for the identification of compounds and/or genes that have highly correlated response patterns for any selected ‘seed’ compound. This presentation provides the first public disclosure of the NCI-60 data for this set of novel, targeted, investigational oncology agents. We anticipate that these data will enable comparison between drug sensitivity profiles that could lead to the elucidation of common mechanistic targets or pathways, associations with potential response biomarkers, the confirmation of mechanism of action or identification of novel mechanisms, and the uncovering of unexpected "off-target" activities. For example, Akt, pI3K, PDK, and mTOR inhibitors, multiple agents targeting one signaling pathway, display strong correlations with one another. Using the allosteric Akt inhibitor MK-2206 as the seed compound, response patterns for the ATP-competitive Akt inhibitors PF-4173640 (0.84), GDC-0068 (0.80), AZD-5363 (0.83), GSK-690693 (0.67), and CCT-128930 (0.69) are highly correlative. Moreover, the NCI-60 response pattern for the androgen receptor modulator AZD-3514 has a 0.77 correlation with the BET bromodomain inhibitor JQ-1, suggesting a commonality of target/pathway for these compounds. Further correlations, associations and hypotheses generated from interrogating the compound response patterns, gene expression profiles, mutations and other characteristics will be presented. Funded by NCI Contract No. HHSN261200800001E. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A102. Citation Format: Joel Morris, Mark Kunkel, Eric Polley, Susan Holbeck, Kazimierz Wrzeszczynski, Anne Monks, David Evans, Annamaria Rapisarda, Jerry Collins, Beverly A. Teicher. NCI-60 response profiles of >400 investigational oncology agents: A resource enabling drug and biomarker discovery. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A102.