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- Title
Signature-based small molecule screening identifies cytosine arabinoside as an EWS/FLI modulator in Ewing sarcoma.
- Authors
Stegmaier, Kimberly; Wong, Jenny S.; Ross, Kenneth N.; Chow, Kwan T.; Peck, David; Wright, Renee D.; Lessnick, Stephen L.; Kung, Andrew L.; Golub, Todd R.
- Abstract
<bold>Background: </bold>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.<bold>Methods and Findings: </bold>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.<bold>Conclusions: </bold>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.
- Subjects
GOLUB, Todd; GENE expression; MOLECULES; DRUGS; CANCER; MYC proteins; THERAPEUTIC use of antimetabolites; ANIMAL experimentation; ANTIMETABOLITES; ANTINEOPLASTIC agents; BONE tumors; CELL lines; PHYSICAL &; theoretical chemistry; COMPARATIVE studies; DRUG delivery systems; CLINICAL drug trials; FLUORIMETRY; GENE amplification; GENES; LATEX; RESEARCH methodology; MEDICAL cooperation; MICE; MOLECULAR structure; OSTEOSARCOMA; PROTEINS; RESEARCH; RESEARCH funding; TRANSCRIPTION factors; EVALUATION research; GENE expression profiling; CYTARABINE; FLUORESCENT dyes; PHARMACODYNAMICS; THERAPEUTICS
- Publication
PLoS Medicine, 2007, Vol 4, Issue 4, pe122
- ISSN
1549-1277
- Publication type
journal article
- DOI
10.1371/journal.pmed.0040122