<?xml version="1.0" encoding="UTF-8"?><xml><records><record><source-app name="Biblio" version="6.x">Drupal-Biblio</source-app><ref-type>17</ref-type><contributors><authors><author><style face="normal" font="default" size="100%">Stegmaier,Kimberly</style></author><author><style face="normal" font="default" size="100%">Wong,Jenny S</style></author><author><style face="normal" font="default" size="100%">Ross,Kenneth N</style></author><author><style face="normal" font="default" size="100%">Chow,Kwan T</style></author><author><style face="normal" font="default" size="100%">Peck,David</style></author><author><style face="normal" font="default" size="100%">Wright,Renee D</style></author><author><style face="normal" font="default" size="100%">Lessnick,Stephen L</style></author><author><style face="normal" font="default" size="100%">Kung,Andrew L</style></author><author><style face="normal" font="default" size="100%">Golub,Todd R</style></author></authors></contributors><titles><title><style face="normal" font="default" size="100%">Signature-based small molecule screening identifies cytosine arabinoside as an EWS/FLI modulator in Ewing sarcoma</style></title><secondary-title><style face="normal" font="default" size="100%">PLoS Medicine</style></secondary-title></titles><keywords><keyword><style  face="normal" font="default" size="100%">Animals</style></keyword><keyword><style  face="normal" font="default" size="100%">Antimetabolites</style></keyword><keyword><style  face="normal" font="default" size="100%">Antineoplastic</style></keyword><keyword><style  face="normal" font="default" size="100%">Antitumor</style></keyword><keyword><style  face="normal" font="default" size="100%">Bone Neoplasms</style></keyword><keyword><style  face="normal" font="default" size="100%">Cancer</style></keyword><keyword><style  face="normal" font="default" size="100%">Cell Line</style></keyword><keyword><style  face="normal" font="default" size="100%">Cytarabine</style></keyword><keyword><style  face="normal" font="default" size="100%">Drug Delivery Systems</style></keyword><keyword><style  face="normal" font="default" size="100%">Drug Screening Assays</style></keyword><keyword><style  face="normal" font="default" size="100%">Fluorescent Dyes</style></keyword><keyword><style  face="normal" font="default" size="100%">Fluorometry</style></keyword><keyword><style  face="normal" font="default" size="100%">Gene Amplification</style></keyword><keyword><style  face="normal" font="default" size="100%">Gene Expression Profiling</style></keyword><keyword><style  face="normal" font="default" size="100%">Gene Expression Regulation</style></keyword><keyword><style  face="normal" font="default" size="100%">Neop</style></keyword><keyword><style  face="normal" font="default" size="100%">Tumor</style></keyword></keywords><dates><year><style  face="normal" font="default" size="100%">2007</style></year><pub-dates><date><style  face="normal" font="default" size="100%">2007/04//</style></date></pub-dates></dates><urls><web-urls><url><style face="normal" font="default" size="100%">http://www.ncbi.nlm.nih.gov/pubmed/17425403</style></url></web-urls></urls><volume><style face="normal" font="default" size="100%">4</style></volume><pages><style face="normal" font="default" size="100%">e122 - e122</style></pages><isbn><style face="normal" font="default" size="100%">1549-1676</style></isbn><language><style face="normal" font="default" size="100%">eng</style></language><abstract><style face="normal" font="default" size="100%">BACKGROUND: The presence of tumor-specific mutations in the cancer genome represents a potential opportunity for pharmacologic intervention to therapeutic benefit. Unfortunately, many classes of oncoproteins (e.g., transcription factors) are not amenable to conventional small-molecule screening. Despite the identification of tumor-specific somatic mutations, most cancer therapy still utilizes nonspecific, cytotoxic drugs. One illustrative example is the treatment of Ewing sarcoma. Although the EWS/FLI oncoprotein, present in the vast majority of Ewing tumors, was characterized over ten years ago, it has never been exploited as a target of therapy. Previously, this target has been intractable to modulation with traditional small-molecule library screening approaches. Here we describe a gene expression-based approach to identify compounds that induce a signature of EWS/FLI attenuation. We hypothesize that screening small-molecule libraries highly enriched for FDA-approved drugs will provide a more rapid path to clinical application. METHODS AND FINDINGS: A gene expression signature for the EWS/FLI off state was determined with microarray expression profiling of Ewing sarcoma cell lines with EWS/FLI-directed RNA interference. A small-molecule library enriched for FDA-approved drugs was screened with a high-throughput, ligation-mediated amplification assay with a fluorescent, bead-based detection. Screening identified cytosine arabinoside (ARA-C) as a modulator of EWS/FLI. ARA-C reduced EWS/FLI protein abundance and accordingly diminished cell viability and transformation and abrogated tumor growth in a xenograft model. Given the poor outcomes of many patients with Ewing sarcoma and the well-established ARA-C safety profile, clinical trials testing ARA-C are warranted. CONCLUSIONS: We demonstrate that a gene expression-based approach to small-molecule library screening can identify, for rapid clinical testing, candidate drugs that modulate previously intractable targets. Furthermore, this is a generic approach that can, in principle, be applied to the identification of modulators of any tumor-associated oncoprotein in the rare pediatric malignancies, but also in the more common adult cancers.</style></abstract><issue><style face="normal" font="default" size="100%">4</style></issue></record></records></xml>
