Overcoming resistance to conventional drugs in Ewing sarcoma and identification of molecular predictors of outcome

Katia Scotlandi, Daniel Remondini, Gastone Castellani, Maria Cristina Manara, Filippo Nardi, Lara Cantiani, Mirko Francesconi, Mario Mercuri, Anna Maria Caccuri, Massimo Serra, Sakari Knuutila, Piero Picci

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)2209-2216
Number of pages8
JournalJournal of Clinical Oncology
Volume27
Issue number13
DOIs
Publication statusPublished - May 1 2009

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

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    Scotlandi, K., Remondini, D., Castellani, G., Manara, M. C., Nardi, F., Cantiani, L., Francesconi, M., Mercuri, M., Caccuri, A. M., Serra, M., Knuutila, S., & Picci, P. (2009). Overcoming resistance to conventional drugs in Ewing sarcoma and identification of molecular predictors of outcome. Journal of Clinical Oncology, 27(13), 2209-2216. https://doi.org/10.1200/JCO.2008.19.2542