Abstract
Ewing's sarcoma family of tumors (EFT) is characterized by the presence of chromosomal translocations leading to the expression of oncogenic transcription factors such as, in the majority of cases, EWS/FLI1. Because of its key role in Ewing's sarcoma development and maintenance, EWS/FLI1 represents an attractive therapeutic target. Here, we characterize PHLDA1 as a novel direct target gene whose expression is repressed by EWS/FLI1. Using this gene and additional specific well-characterized target genes such as NROB1, NKX2.2 and CAV1, all activated by EWS/FLI1, as a read-out system, we screened a small-molecule compound library enriched for FDA-approved drugs that modulated the expression of EWS/FLI1 target genes. Among a hit-list of nine well-known drugs such as camptothecin, fenretinide, etoposide and doxorubicin, we also identified the kinase inhibitor midostaurin (PKC412). Subsequent experiments demonstrated that midostaurin is able to induce apoptosis in a panel of six Ewing's sarcoma cell lines in vitro and can significantly suppress xenograft tumor growth in vivo. These results suggest that midostaurin might be a novel drug that is active against Ewing's cells, which might act by modulating the expression of EWS/FLI1 target genes.
Copyright © 2012 UICC.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Caveolin 1 / genetics
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Cell Line, Tumor
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Cell Survival
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Enzyme Inhibitors / pharmacology
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Gene Expression Regulation, Neoplastic / drug effects*
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Homeobox Protein Nkx-2.2
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Homeodomain Proteins / genetics
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Humans
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Mice
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Mice, Inbred NOD
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Nuclear Proteins
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / metabolism*
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Proto-Oncogene Protein c-fli-1 / genetics
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Proto-Oncogene Protein c-fli-1 / metabolism*
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RNA Interference
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RNA, Small Interfering
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RNA-Binding Protein EWS / genetics
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RNA-Binding Protein EWS / metabolism*
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Random Allocation
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Sarcoma, Ewing / metabolism*
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Sarcoma, Ewing / pathology*
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Small Molecule Libraries
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Staurosporine / analogs & derivatives*
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Staurosporine / pharmacology
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Xenograft Model Antitumor Assays
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Zebrafish Proteins
Substances
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Antineoplastic Agents
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CAV1 protein, human
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Caveolin 1
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EWS-FLI fusion protein
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Enzyme Inhibitors
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Homeobox Protein Nkx-2.2
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Homeodomain Proteins
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NKX2-2 protein, human
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Nkx2-2 protein, mouse
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Nuclear Proteins
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Oncogene Proteins, Fusion
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PHLDA1 protein, human
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Proto-Oncogene Protein c-fli-1
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RNA, Small Interfering
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RNA-Binding Protein EWS
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Small Molecule Libraries
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Transcription Factors
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Zebrafish Proteins
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nkx2.2b protein, zebrafish
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Staurosporine
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midostaurin