Originally published as JCO Early Release 10.1200/JCO.2008.19.2542 on March 23 2009

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Overcoming Resistance to Conventional Drugs in Ewing Sarcoma and Identification of Molecular Predictors of Outcome

From the Department of Oncology, Orthopaedic Institute Rizzoli; Department of Veterinary Morphophysiology and Animal Production and Department of Physics, University of Bologna, Bologna; Department of Science and Chemical Technologies, Università Tor Vergata, Roma, Italy; and Department of Pathology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.

Corresponding author: Katia Scotlandi, PhD, Laboratory of Oncologic Research, Orthopaedic Institute Rizzoli, Via di Barbiano 1/10, 40136 Bologna, Italy; e-mail: katia.scotlandi{at}ior.it.

Purpose The improvement of Ewing sarcoma (EWS) therapy is currently linked to the discovery of strategies to select patients with poor and good prognosis and of modified treatment regimens. In this study, we analyzed the molecular factors governing EWS response to chemotherapy to identify genetic signatures to be used for risk-adapted therapy.

Patients and Methods Microarray technology was used for profiling 30 primary tumors and seven metastases of patients who were classified according to event-free survival. For selected genes, real-time polymerase chain reaction was applied in 42 EWS primary tumors as validation assay. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test was used to evaluate in vitro drug sensitivity.

Results We identified molecular signatures that reflect tumor resistance to chemotherapy. Annotation analysis was applied to reveal the biologic functions that critically influenced clinical outcome. The prognostic relevance of glutathione metabolism pathway was validated. The expression of MGST1, the microsomal glutathione S-transferase (GST), was found to clearly predict EWS prognosis. MGST1 expression was associated with doxorubicin chemosensitivity. This prompted us to assess the in vitro effectiveness of 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX), a new anticancer agent that efficiently inhibits GST enzymes. Six cell lines were found to be sensitive to this new drug.

Conclusion Classification of EWS patients into high- and low-risk groups is feasible with restricted molecular signatures that may have practical value at diagnosis for selecting patients with EWS who are unresponsive to current treatments. Glutathione metabolism pathway emerged as one of the most significantly altered prognosis-associated pathway. NBDHEX is proposed as a new potential therapeutic possibility.

Supported by the European Project PROTHETS (Grant No. 503036), the Italian Association for Cancer Research (grant to K.S.), the Italian Ministry of Health (Alliance against Cancer to P.P.), and the Italian Ministry of University and Research (Grant No. PRIN 2007 to M.M.).

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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