Abstract 2547: NCI-60 combination screening matrix of approved anticancer drugs

Abstract

Abstract Anticancer drugs are rarely curative as single agents, thus most treatment regimens utilize a combination of agents. Selection of rational combinations based upon presumed mechanisms of action is an active area of research. Nonetheless, treatment regimens may have built up over time by addition of new agents to existing standards of care. In order to establish a framework for extending our understanding combination therapy, we have initiated an additional approach: the systematic testing of all pairwise combinations of FDA-approved anticancer drugs in the NCI-60 panel of human tumor cell lines. About 100 small molecule drugs are approved for cancer treatment worldwide – testing all 5000 pairwise combinations in each of 60 cell lines will require 300,000 experiments. Combinations are tested at 3 or more concentrations of each agent, and single agents are tested on the same plates, requiring ∼ 5 million wells. To date, about 100 pairs of drugs have been tested in the NCI-60 in a pilot phase – the high-throughput phase has just begun. Some combinations of drugs, such as bortezomib combined with cladribine, show better than single agent activity in nearly all cell lines tested. Other combinations, such as doxorubicin plus lapatinib, show more restricted benefit, with some cell lines showing enhanced growth inhibition or cell kill, while in other cell lines the combination is antagonistic or identical to the more active single agent. The NCI-60 panel of cell lines has been extensively molecularly characterized, with publicly available data including gene mutation, DNA copy number, DNA methylation, and expression of mRNA, protein and microRNA. The patterns of cell line sensitivity for a particular drug combination can be used to probe these molecular characterization data, generating hypotheses about potential predictive markers and/or mechanisms of action. Probing the doxorubicin plus lapatinib patterns reveals a strong correlation with MDR activity, with high MDR expressing lines showing enhanced combination activity. The most promising combinations identified from NCI-60 testing are being tested in vivo to determine the therapeutic index. Already 2 combinations have demonstrated promising xenograft activity. The combination screening data, along with tools to analyze the data, will be made available to the public through the NCI web site. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2547. doi:10.1158/1538-7445.AM2011-2547