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Optimal Management of Ewing Sarcoma Family of Tumors: Recent Developments in Systemic Therapy

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Abstract

The Ewing sarcoma family of tumors (ESFT) is defined by cell surface expression of CD99 and a translocation involving EWS and an ETS partner. Cytotoxic chemotherapy remains the benchmark of first- and second-line therapy, and although the majority of patients with localized disease are cured, almost one third of patients relapse or progress from their disease. Moreover, cure remains elusive in most patients who present with distant metastases. In recent years, the ESFT literature has been dominated by reports of attempts at modulating the insulin-like growth factor (IGF) receptor (IGFR). Unfortunately, three phase II studies examining inhibiting antibodies to IGFR-1 published disappointing results. Whether these results were due to failure to modulate the pathway or other limitations in study design and/or patient selection remain unclear. Other novel strategies currently being investigated in ESFT include tyrosine kinase, mammalian target of rapamycin (mTOR), and poly(ADP-ribose) polymerase (PARP) inhibitors.

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References

  1. Dehner LP. Primitive neuroectodermal tumor and Ewing’s sarcoma. Am J Surg Pathol. 1993;17(1):1–13.

    CAS  PubMed  Google Scholar 

  2. Ewing J. The Classic: diffuse endothelioma of bone. Proceedings of the New York Pathological Society. 1921;12:17. Clin Orthop Relat Res. 2006;450:25–7.

    PubMed  Google Scholar 

  3. Balamuth NJ, Womer RB. Ewing’s sarcoma. Lancet Oncol. 2010;11(2):184–92.

    CAS  PubMed  Google Scholar 

  4. Delattre O, Zucman J, Plougastel B, et al. Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours. Nature. 1992;359(6391):162–5.

    CAS  PubMed  Google Scholar 

  5. Bernstein M, Kovar H, Paulussen M, et al. Ewing’s sarcoma family of tumors: current management. Oncologist. 2006;11(5):503–19.

    CAS  PubMed  Google Scholar 

  6. Gurney JG, Swensen AR, Bulterys M. Malignant bone tumors. In: Ries LAG, Smith MA, Gurney, et al., editors. Cancer incidence and survival among children and adolescents: United States SEER Program 1975–1995. NIH Pub. No. 99-4649. Bethesda: National Institutes of Health; 1999. p. 99–110.

  7. Dahlin DC, Coventry MB, Scanlon PW. Ewing’s sarcoma: a critical analysis of 165 cases. J Bone Joint Surg Am. 1961;43-A:185–92.

    CAS  PubMed  Google Scholar 

  8. Womer RB, West DC, Krailo MD, et al. Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma: a report from the Children’s Oncology Group. J Clin Oncol. 2012;30(33):4148–54.

    CAS  PubMed  Google Scholar 

  9. Cotterill SJ, Ahrens S, Paulussen M, et al. Prognostic factors in Ewing’s tumor of bone: analysis of 975 patients from the European Intergroup Cooperative Ewing’s Sarcoma Study Group. J Clin Oncol. 2000;18(17):3108–14.

    CAS  PubMed  Google Scholar 

  10. Miser JS, Krailo MD, Tarbell NJ, et al. Treatment of metastatic Ewing’s sarcoma or primitive neuroectodermal tumor of bone: evaluation of combination ifosfamide and etoposide: a Children’s Cancer Group and Pediatric Oncology Group study. J Clin Oncol. 2004;22(14):2873–6.

    CAS  PubMed  Google Scholar 

  11. Ladenstein R, Potschger U, Le Deley MC, et al. Primary disseminated multifocal Ewing sarcoma: results of the Euro-EWING 99 trial. J Clin Oncol. 2010;28(20):3284–91.

    CAS  PubMed  Google Scholar 

  12. Haeusler J, Ranft A, Boelling T, et al. The value of local treatment in patients with primary, disseminated, multifocal Ewing sarcoma (PDMES). Cancer. 2010;116(2):443–50.

    PubMed  Google Scholar 

  13. Paulussen M, Ahrens S, Burdach S, et al. Primary metastatic (stage IV) Ewing tumor: survival analysis of 171 patients from the EICESS studies. European Intergroup Cooperative Ewing Sarcoma Studies. Ann Oncol. 1998;9(3):275–81.

    CAS  PubMed  Google Scholar 

  14. Grier HE, Krailo MD, Tarbell NJ, et al. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing’s sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med. 2003;348(8):694–701.

    CAS  PubMed  Google Scholar 

  15. Granowetter L, Womer R, Devidas M, et al. Dose-intensified compared with standard chemotherapy for nonmetastatic Ewing sarcoma family of tumors: a Children’s Oncology Group Study. J Clin Oncol. 2009;27(15):2536–41.

    CAS  PubMed  Google Scholar 

  16. Oberlin O, Deley MC, Bui BN, et al. Prognostic factors in localized Ewing’s tumours and peripheral neuroectodermal tumours: the third study of the French Society of Paediatric Oncology (EW88 study). Br J Cancer. 2001;85(11):1646–54.

    CAS  PubMed  Google Scholar 

  17. Rodriguez-Galindo C, Liu T, Krasin MJ, et al. Analysis of prognostic factors in Ewing sarcoma family of tumors: review of St. Jude Children’s Research Hospital studies. Cancer. 2007;110(2):375–84.

    PubMed  Google Scholar 

  18. Gupta AA, Pappo A, Saunders N, et al. Clinical outcome of children and adults with localized Ewing sarcoma: impact of chemotherapy dose and timing of local therapy. Cancer. 2010;116(13):3189–94.

    PubMed  Google Scholar 

  19. Lee J, Hoang BH, Ziogas A, Zell JA. Analysis of prognostic factors in Ewing sarcoma using a population-based cancer registry. Cancer. 2010;116(8):1964–73.

    PubMed  Google Scholar 

  20. Strauss SJ, McTiernan A, Driver D, et al. Single center experience of a new intensive induction therapy for Ewing’s family of tumors: feasibility, toxicity, and stem cell mobilization properties. J Clin Oncol. 2003;21(15):2974–81.

    CAS  PubMed  Google Scholar 

  21. Oberlin O, Le Deley M, Dirksen U, Lewis IJ, Ranft A, Michon JM, et al. Randomized comparison of VAC versus VAI chemotherapy (CT) as consolidation for standard risk (SR) Ewing sarcoma tumor (ES): results of the Euro-EWING.99-R1 trial [American Society of Clinical Oncology meeting abstract]. J Clin Oncol. 2011;15S:9517.

    Google Scholar 

  22. Combination chemotherapy with or without peripheral stem cell transplantation, radiation therapy, and/or surgery in treating patients with Ewing’s sarcoma (Euro-EWING 99) [NCT00020566]. http://www.clinicaltrials.gov/ct2/show/NCT00020566 (Accessed 10 Jul 2012).

  23. Miser JS, Goldsby RE, Chen Z, et al. Treatment of metastatic Ewing sarcoma/primitive neuroectodermal tumor of bone: evaluation of increasing the dose intensity of chemotherapy: a report from the Children’s Oncology Group. Pediatr Blood Cancer. 2007;49(7):894–900.

    PubMed  Google Scholar 

  24. Paulussen M, Ahrens S, Craft AW, et al. Ewing’s tumors with primary lung metastases: survival analysis of 114 (European Intergroup) Cooperative Ewing’s Sarcoma Studies patients. J Clin Oncol. 1998;16(9):3044–52.

    CAS  PubMed  Google Scholar 

  25. Nesbit ME Jr, Gehan EA, Burgert EO Jr, et al. Multimodal therapy for the management of primary, nonmetastatic Ewing’s sarcoma of bone: a long-term follow-up of the First Intergroup study. J Clin Oncol. 1990;8(10):1664–74.

    PubMed  Google Scholar 

  26. Paulussen M, Braun-Munzinger G, Burdach S, et al. Results of treatment of primary exclusively pulmonary metastatic Ewing sarcoma. A retrospective analysis of 41 patients (in German). Klin Padiatr. 1993;205(4):210–6.

    CAS  PubMed  Google Scholar 

  27. Pinkerton CR, Bataillard A, Guillo S, Oberlin O, Fervers B, Philip T. Treatment strategies for metastatic Ewing’s sarcoma. Eur J Cancer. 2001;37(11):1338–44.

    CAS  PubMed  Google Scholar 

  28. Bolling T, Schuck A, Paulussen M, et al. Whole lung irradiation in patients with exclusively pulmonary metastases of Ewing tumors: toxicity analysis and treatment results of the EICESS-92 trial. Strahlenther Onkol. 2008;184(4):193–7.

    PubMed  Google Scholar 

  29. Spunt SL, McCarville MB, Kun LE, et al. Selective use of whole-lung irradiation for patients with Ewing sarcoma family tumors and pulmonary metastases at the time of diagnosis. J Pediatr Hematol Oncol. 2001;23(2):93–8.

    CAS  PubMed  Google Scholar 

  30. Oberlin O, Rey A, Desfachelles AS, et al. Impact of high-dose busulfan plus melphalan as consolidation in metastatic Ewing tumors: a study by the Societe Francaise des Cancers de l’Enfant. J Clin Oncol. 2006;24(24):3997–4002.

    CAS  PubMed  Google Scholar 

  31. Ladenstein R, Lasset C, Pinkerton R, et al. Impact of megatherapy in children with high-risk Ewing’s tumours in complete remission: a report from the EBMT Solid Tumour Registry. Bone Marrow Transplant. 1995;15(5):697–705.

    CAS  PubMed  Google Scholar 

  32. Meyers PA, Krailo MD, Ladanyi M, et al. High-dose melphalan, etoposide, total-body irradiation, and autologous stem-cell reconstitution as consolidation therapy for high-risk Ewing’s sarcoma does not improve prognosis. J Clin Oncol. 2001;19(11):2812–20.

    CAS  PubMed  Google Scholar 

  33. Burdach S, Thiel U, Schoniger M, et al. Total body MRI-governed involved compartment irradiation combined with high-dose chemotherapy and stem cell rescue improves long-term survival in Ewing tumor patients with multiple primary bone metastases. Bone Marrow Transplant. 2010;45(3):483–9.

    CAS  PubMed  Google Scholar 

  34. Owens C, Le Deley MC, Michon J, Marzouk I, Thebault E, Marec-Berard P, Oberlin O. The management of pulmonary nodules at diagnosis in patients with Ewing sarcoma (ES) [American Society of Clinical Oncology meeting abstract]. J Clin Oncol. 2011;15S:9527.

    Google Scholar 

  35. Letourneau PA, Shackett B, Xiao L, et al. Resection of pulmonary metastases in pediatric patients with Ewing sarcoma improves survival. J Pediatr Surg. 2011;46(2):332–5.

    PubMed  Google Scholar 

  36. Shankar AG, Ashley S, Craft AW, Pinkerton CR. Outcome after relapse in an unselected cohort of children and adolescents with Ewing sarcoma. Med Pediatr Oncol. 2003;40(3):141–7.

    CAS  PubMed  Google Scholar 

  37. Rodriguez-Galindo C, Billups CA, Kun LE, et al. Survival after recurrence of Ewing tumors: the St Jude Children’s Research Hospital experience, 1979–1999. Cancer. 2002;94(2):561–9.

    PubMed  Google Scholar 

  38. Leavey PJ, Mascarenhas L, Marina N, et al. Prognostic factors for patients with Ewing sarcoma (EWS) at first recurrence following multi-modality therapy: a report from the Children’s Oncology Group. Pediatr Blood Cancer. 2008;51(3):334–8.

    PubMed  Google Scholar 

  39. Bacci G, Ferrari S, Longhi A, et al. Therapy and survival after recurrence of Ewing’s tumors: the Rizzoli experience in 195 patients treated with adjuvant and neoadjuvant chemotherapy from 1979 to 1997. Ann Oncol. 2003;14(11):1654–9.

    CAS  PubMed  Google Scholar 

  40. Cersosimo RJ. Topotecan: a new topoisomerase I inhibiting antineoplastic agent. Ann Pharmacother. 1998;32(12):1334–43.

    CAS  PubMed  Google Scholar 

  41. Saylors RL 3rd, Stewart CF, Zamboni WC, et al. Phase I study of topotecan in combination with cyclophosphamide in pediatric patients with malignant solid tumors: a Pediatric Oncology Group Study. J Clin Oncol. 1998;16(3):945–52.

    CAS  PubMed  Google Scholar 

  42. Saylors RL 3rd, Stine KC, Sullivan J, et al. Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. J Clin Oncol. 2001;19(15):3463–9.

    CAS  PubMed  Google Scholar 

  43. Hunold A, Weddeling N, Paulussen M, Ranft A, Liebscher C, Jurgens H. Topotecan and cyclophosphamide in patients with refractory or relapsed Ewing tumors. Pediatr Blood Cancer. 2006;47(6):795–800.

    PubMed  Google Scholar 

  44. Bernstein ML, Devidas M, Lafreniere D, et al. Intensive therapy with growth factor support for patients with Ewing tumor metastatic at diagnosis: Pediatric Oncology Group/Children’s Cancer Group phase II study 9457—a report from the Children’s Oncology Group. J Clin Oncol. 2006;24(1):152–9.

    CAS  PubMed  Google Scholar 

  45. Blanchette P, Hogg D, Ferguson P, et al. Topotecan and cyclophosphamide in adults with relapsed sarcoma. Sarcoma. 2012;2012:749067.

    CAS  PubMed  Google Scholar 

  46. Combination chemotherapy in treating patients with non-metastatic extracranial Ewing sarcoma (COG AEWS1031 NCT01231906). http://www.clinicaltrials.gov/ct2/show/NCT01231906 (Accessed 10 Jul 2012).

  47. Wagner L. Camptothecin-based regimens for treatment of Ewing sarcoma: past studies and future directions. Sarcoma. 2011;2011:957957.

    PubMed  Google Scholar 

  48. Jones SF, Gian VG, Greco FA, et al. Phase I. Trial of irinotecan and temozolomide in patients with solid tumors. Oncology (Williston Park). 2003;17(5 Suppl 5):41–5.

    Google Scholar 

  49. Reardon DA, Quinn JA, Rich JN, et al. Phase I trial of irinotecan plus temozolomide in adults with recurrent malignant glioma. Cancer. 2005;104(7):1478–86.

    CAS  PubMed  Google Scholar 

  50. Kushner BH, Kramer K, Modak S, Cheung NK. Irinotecan plus temozolomide for relapsed or refractory neuroblastoma. J Clin Oncol. 2006;24(33):5271–6.

    CAS  PubMed  Google Scholar 

  51. Newlands ES, Stevens MF, Wedge SR, Wheelhouse RT, Brock C. Temozolomide: a review of its discovery, chemical properties, pre-clinical development and clinical trials. Cancer Treat Rev. 1997;23(1):35–61.

    CAS  PubMed  Google Scholar 

  52. Wagner LM, McAllister N, Goldsby RE, et al. Temozolomide and intravenous irinotecan for treatment of advanced Ewing sarcoma. Pediatr Blood Cancer. 2007;48(2):132–9.

    PubMed  Google Scholar 

  53. Casey DA, Wexler LH, Merchant MS, et al. Irinotecan and temozolomide for Ewing sarcoma: the Memorial Sloan-Kettering experience. Pediatr Blood Cancer. 2009;53(6):1029–34.

    PubMed  Google Scholar 

  54. Wagner LM. Oral irinotecan for treatment of pediatric solid tumors: ready for prime time? Pediatr Blood Cancer. 2010;54(5):661–2.

    PubMed  Google Scholar 

  55. Hensley ML, Maki R, Venkatraman E, et al. Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma: results of a phase II trial. J Clin Oncol. 2002;20(12):2824–31.

    CAS  PubMed  Google Scholar 

  56. Mini E, Nobili S, Caciagli B, Landini I, Mazzei T. Cellular pharmacology of gemcitabine. Ann Oncol. 2006;17(Suppl 5):v7–12.

    PubMed  Google Scholar 

  57. Maki RG. Gemcitabine and docetaxel in metastatic sarcoma: past, present, and future. Oncologist. 2007;12(8):999–1006.

    CAS  PubMed  Google Scholar 

  58. Lyseng-Williamson KA, Fenton C. Docetaxel: a review of its use in metastatic breast cancer. Drugs. 2005;65(17):2513–31.

    CAS  PubMed  Google Scholar 

  59. Mora J, Cruz CO, Parareda A, de Torres C. Treatment of relapsed/refractory pediatric sarcomas with gemcitabine and docetaxel. J Pediatr Hematol Oncol. 2009;31(10):723–9.

    CAS  PubMed  Google Scholar 

  60. Fox E, Patel S, Wathen JK, et al. Phase II study of sequential gemcitabine followed by docetaxel for recurrent Ewing sarcoma, osteosarcoma, or unresectable or locally recurrent chondrosarcoma: results of Sarcoma Alliance for Research Through Collaboration Study 003. Oncologist. 2012;17(3):e321–9.

    Google Scholar 

  61. Turc-Carel C, Philip I, Berger MP, Philip T, Lenoir G. Chromosomal translocation (11; 22) in cell lines of Ewing’s sarcoma [in French]. C R Seances Acad Sci III. 1983;296(23):1101–3.

    CAS  PubMed  Google Scholar 

  62. Aurias A, Rimbaut C, Buffe D, Dubousset J, Mazabraud A. Translocation of chromosome 22 in Ewing’s sarcoma (in French). C R Seances Acad Sci III. 1983;296(23):1105–7.

    CAS  PubMed  Google Scholar 

  63. Lessnick SL, Ladanyi M. Molecular pathogenesis of Ewing sarcoma: new therapeutic and transcriptional targets. Ann Rev Pathol. 2012;7:145–59.

    CAS  Google Scholar 

  64. Toomey EC, Schiffman JD, Lessnick SL. Recent advances in the molecular pathogenesis of Ewing’s sarcoma. Oncogene. 2010;29(32):4504–16.

    CAS  PubMed  Google Scholar 

  65. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.

    CAS  PubMed  Google Scholar 

  66. Potratz J, Jurgens H, Craft A, Dirksen U. Ewing sarcoma: biology-based therapeutic perspectives. Pediatr Hematol Oncol. 2012;29(1):12–27.

    CAS  PubMed  Google Scholar 

  67. Pinto A, Dickman P, Parham D. Pathobiologic markers of the Ewing sarcoma family of tumors: state of the art and prediction of behaviour. Sarcoma. 2011;2011:856190.

    PubMed  Google Scholar 

  68. Janknecht R. EWS–ETS oncoproteins: the linchpins of Ewing tumors. Gene. 2005;363:1–14.

    CAS  PubMed  Google Scholar 

  69. Mackintosh C, Madoz-Gurpide J, Ordonez JL, Osuna D, Herrero-Martin D. The molecular pathogenesis of Ewing’s sarcoma. Cancer Biol Ther. 2010;9(9):655–67.

    CAS  PubMed  Google Scholar 

  70. Smith R, Owen LA, Trem DJ, et al. Expression profiling of EWS/FLI identifies NKX2.2 as a critical target gene in Ewing’s sarcoma. Cancer Cell. 2006;9(5):405–16.

    CAS  PubMed  Google Scholar 

  71. Owen LA, Kowalewski AA, Lessnick SL. EWS/FLI mediates transcriptional repression via NKX2.2 during oncogenic transformation in Ewing’s sarcoma. PLoS One. 2008;3(4):e1965.

    PubMed  Google Scholar 

  72. Keshelava N, Houghton PJ, Morton CL, et al. Initial testing (stage 1) of vorinostat (SAHA) by the pediatric preclinical testing program. Pediatr Blood Cancer. 2009;53(3):505–8.

    PubMed  Google Scholar 

  73. Sakimura R, Tanaka K, Nakatani F, et al. Antitumor effects of histone deacetylase inhibitor on Ewing’s family tumors. Int J Cancer. 2005;116(5):784–92.

    CAS  PubMed  Google Scholar 

  74. Sonnemann J, Dreyer L, Hartwig M, et al. Histone deacetylase inhibitors induce cell death and enhance the apoptosis-inducing activity of TRAIL in Ewing’s sarcoma cells. J Cancer Res Clin Oncol. 2007;133(11):847–58.

    CAS  PubMed  Google Scholar 

  75. Valproic acid in treating young patients with recurrent or refractory solid tumors or CNS tumors (NCI ADVL04190 [NCT00107458]). http://www.clinicaltrials.gov/ct2/show/NCT00107458 (Accessed 10 Jul 2012).

  76. Vorinostat in children [NCT01422499]. http://www.clinicaltrials.gov/cts/show/NCT01422499 (Accessed 10 Jul 2012).

  77. Shahi MH, Schiapparelli P, Afzal M, Sinha S, Rey JA, Castresana JS. Expression and epigenetic modulation of sonic hedgehog-GLI1 pathway genes in neuroblastoma cell lines and tumors. Tumour Biol. 2011;32(1):113–27.

    CAS  PubMed  Google Scholar 

  78. Beauchamp EM, Ringer L, Bulut G, et al. Arsenic trioxide inhibits human cancer cell growth and tumor development in mice by blocking Hedgehog/GLI pathway. J Clin Invest. 2011;121(1):148–60.

    CAS  PubMed  Google Scholar 

  79. Smith MA, Kang MH, Reynolds CP, et al. Evaluation of arsenic trioxide by the pediatric preclinical testing program with a focus on Ewing sarcoma. Pediatr Blood Cancer. 2012;59(4):753–5.

    PubMed  Google Scholar 

  80. Kinsey M, Smith R, Lessnick SL. NR0B1 is required for the oncogenic phenotype mediated by EWS/FLI in Ewing’s sarcoma. Mol Cancer Res. 2006;4(11):851–9.

    CAS  PubMed  Google Scholar 

  81. Garcia-Aragoncillo E, Carrillo J, Lalli E, et al. DAX1, a direct target of EWS/FLI1 oncoprotein, is a principal regulator of cell-cycle progression in Ewing’s tumor cells. Oncogene. 2008;27(46):6034–43.

    CAS  PubMed  Google Scholar 

  82. D’Incalci M, Galmarini CM. A review of trabectedin (ET-743): a unique mechanism of action. Mol Cancer Ther. 2010;9(8):2157–63.

    PubMed  Google Scholar 

  83. Grohar PJ, Griffin LB, Yeung C, et al. Ecteinascidin 743 interferes with the activity of EWS–FLI1 in Ewing sarcoma cells. Neoplasia. 2011;13(2):145–53.

    CAS  PubMed  Google Scholar 

  84. Lau L, Supko JG, Blaney S, et al. A phase I and pharmacokinetic study of ecteinascidin-743 (Yondelis) in children with refractory solid tumors: a Children’s Oncology Group study. Clin Cancer Res. 2005;11(2 Pt 1):672–7.

    CAS  PubMed  Google Scholar 

  85. Baruchel S, Pappo A, Krailo M, et al. A phase 2 trial of trabectedin in children with recurrent rhabdomyosarcoma, Ewing sarcoma and non-rhabdomyosarcoma soft tissue sarcomas: a report from the Children’s Oncology Group. Eur J Cancer. 2012;48(4):579–85.

    CAS  PubMed  Google Scholar 

  86. Kovar H. Ewing tumor biology: perspectives for innovative treatment approaches. Adv Exp Med Biol. 2003;532:27–37.

    CAS  PubMed  Google Scholar 

  87. Kelleher FC, Thomas DM. Molecular pathogenesis and targeted therapeutics in Ewing sarcoma/primitive neuroectodermal tumours. Clin Sarcoma Res. 2012;2(1):6.

    CAS  PubMed  Google Scholar 

  88. Kovar H, Aryee DN, Jug G, et al. EWS/FLI-1 antagonists induce growth inhibition of Ewing tumor cells in vitro. Cell Growth Differ. 1996;7(4):429–37.

    CAS  PubMed  Google Scholar 

  89. Tanaka K, Iwakuma T, Harimaya K, Sato H, Iwamoto Y. EWS–Fli1 antisense oligodeoxynucleotide inhibits proliferation of human Ewing’s sarcoma and primitive neuroectodermal tumor cells. J Clin Invest. 1997;99(2):239–47.

    CAS  PubMed  Google Scholar 

  90. Chansky HA, Barahmand-Pour F, Mei Q, et al. Targeting of EWS/FLI-1 by RNA interference attenuates the tumor phenotype of Ewing’s sarcoma cells in vitro. J Orthop Res. 2004;22(4):910–7.

    CAS  PubMed  Google Scholar 

  91. Mateo-Lozano S, Gokhale PC, Soldatenkov VA, Dritschilo A, Tirado OM, Notario V. Combined transcriptional and translational targeting of EWS/FLI-1 in Ewing’s sarcoma. Clin Cancer Res. 2006;12(22):6781–90.

    CAS  PubMed  Google Scholar 

  92. Erkizan HV, Scher LJ, Gamble SE, et al. Novel peptide binds EWS–FLI1 and reduces the oncogenic potential in Ewing tumors. Cell Cycle. 2011;10(19):3397–408.

    CAS  PubMed  Google Scholar 

  93. Garnett MJ, Edelman EJ, Heidorn SJ, et al. Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature. 2012;483(7391):570–5.

    CAS  PubMed  Google Scholar 

  94. Murai J, Huang SY, Das BB, et al. Trapping of PARP1 and PARP2 by clinical PARP inhibitors. Cancer Res. 2012;72(21):5588–99.

    CAS  PubMed  Google Scholar 

  95. Carey LA, Sharpless NE. PARP and cancer: if it’s broke, don’t fix it. N Engl J Med. 2011;364(3):277–9.

    CAS  PubMed  Google Scholar 

  96. Brenner JC, Feng FY, Han S, et al. PARP-1 inhibition as a targeted strategy to treat Ewing’s sarcoma. Cancer Res. 2012;72(7):1608–13.

    CAS  PubMed  Google Scholar 

  97. O’Shaughnessy J, Osborne C, Pippen JE, et al. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med. 2011;364(3):205–14.

    PubMed  Google Scholar 

  98. Lemmon MA, Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell. 2010;141(7):1117–34.

    CAS  PubMed  Google Scholar 

  99. Krause DS, Van Etten RA. Tyrosine kinases as targets for cancer therapy. N Engl J Med. 2005;353(2):172–87.

    CAS  PubMed  Google Scholar 

  100. Doolittle RF, Hunkapiller MW, Hood LE, et al. Simian sarcoma virus onc gene, v-sis, is derived from the gene (or genes) encoding a platelet-derived growth factor. Science. 1983;221(4607):275–7.

    CAS  PubMed  Google Scholar 

  101. Waterfield MD, Scrace GT, Whittle N, et al. Platelet-derived growth factor is structurally related to the putative transforming protein p28sis of simian sarcoma virus. Nature. 1983;304(5921):35–9.

    CAS  PubMed  Google Scholar 

  102. DuBois SG, Marina N, Glade-Bender J. Angiogenesis and vascular targeting in Ewing sarcoma: a review of preclinical and clinical data. Cancer. 2010;116(3):749–57.

    PubMed  Google Scholar 

  103. Dalal S, Berry AM, Cullinane CJ, et al. Vascular endothelial growth factor: a therapeutic target for tumors of the Ewing’s sarcoma family. Clin Cancer Res. 2005;11(6):2364–78.

    CAS  PubMed  Google Scholar 

  104. Kerbel RS. Tumor angiogenesis. N Engl J Med. 2008;358(19):2039–49.

    CAS  PubMed  Google Scholar 

  105. de Castro Junior G, Puglisi F, de Azambuja E, El Saghir NS, Awada A. Angiogenesis and cancer: a cross-talk between basic science and clinical trials (the “do ut des” paradigm). Crit Rev Oncol Hematol. 2006;59(1):40–50.

    PubMed  Google Scholar 

  106. Bid HK, Houghton PJ. Targeting angiogenesis in childhood sarcomas. Sarcoma. 2011;2011:601514.

    PubMed  Google Scholar 

  107. Fuchs B, Inwards CY, Janknecht R. Vascular endothelial growth factor expression is up-regulated by EWS–ETS oncoproteins and Sp1 and may represent an independent predictor of survival in Ewing’s sarcoma. Clin Cancer Res. 2004;10(4):1344–53.

    CAS  PubMed  Google Scholar 

  108. Strammiello R, Benini S, Manara MC, Perdichizzi S, Serra M, Spisni E, et al. Impact of IGF-I/IGF-IR circuit on the angiogenetic properties of Ewing’s sarcoma cells. Horm Metab Res. 2003;35(11–12):675–84.

    CAS  PubMed  Google Scholar 

  109. Simpson A, Grimer R, Mangham C, Cullinane C, Lewis I, Burchill S. MVD predicts disease-free and overall survival in tumours of the Ewing sarcoma family (ESFT) (abstract). Br J Cancer. 2002;86(Suppl 1):S95.

    Google Scholar 

  110. Shawver LK, Slamon D, Ullrich A. Smart drugs: tyrosine kinase inhibitors in cancer therapy. Cancer Cell. 2002;1(2):117–23.

    CAS  PubMed  Google Scholar 

  111. Reichert JM, Valge-Archer VE. Development trends for monoclonal antibody cancer therapeutics. Nat Rev Drug Discov. 2007;6(5):349–56.

    CAS  PubMed  Google Scholar 

  112. Merchant MS, Woo CW, Mackall CL, Thiele CJ. Potential use of imatinib in Ewing’s sarcoma: evidence for in vitro and in vivo activity. J Natl Cancer Inst. 2002;94(22):1673–9.

    CAS  PubMed  Google Scholar 

  113. Maris JM, Courtright J, Houghton PJ, et al. Initial testing (stage 1) of sunitinib by the pediatric preclinical testing program. Pediatr Blood Cancer. 2008;51(1):42–8.

    PubMed  Google Scholar 

  114. Keir ST, Maris JM, Lock R, et al. Initial testing (stage 1) of the multi-targeted kinase inhibitor sorafenib by the pediatric preclinical testing program. Pediatr Blood Cancer. 2010;55(6):1126–33.

    PubMed  Google Scholar 

  115. Bond M, Bernstein ML, Pappo A, et al. A phase II study of imatinib mesylate in children with refractory or relapsed solid tumors: a Children’s Oncology Group study. Pediatr Blood Cancer. 2008;50(2):254–8.

    PubMed  Google Scholar 

  116. Ugurel S, Hildenbrand R, Zimpfer A, et al. Lack of clinical efficacy of imatinib in metastatic melanoma. Br J Cancer. 2005;92(8):1398–405.

    CAS  PubMed  Google Scholar 

  117. Krug LM, Crapanzano JP, Azzoli CG, et al. Imatinib mesylate lacks activity in small cell lung carcinoma expressing c-kit protein: a phase II clinical trial. Cancer. 2005;103(10):2128–31.

    CAS  PubMed  Google Scholar 

  118. Modi S, Seidman AD, Dickler M, et al. A phase II trial of imatinib mesylate monotherapy in patients with metastatic breast cancer. Breast Cancer Res Treat. 2005;90(2):157–63.

    CAS  PubMed  Google Scholar 

  119. Kang MH, Smith MA, Morton CL, Keshelava N, Houghton PJ, Reynolds CP. National Cancer Institute pediatric preclinical testing program: model description for in vitro cytotoxicity testing. Pediatr Blood Cancer. 2011;56(2):239–49.

    PubMed  Google Scholar 

  120. Wilhelm SM, Adnane L, Newell P, Villanueva A, Llovet JM, Lynch M. Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol Cancer Ther. 2008;7(10):3129–40.

    CAS  PubMed  Google Scholar 

  121. Papaetis GS, Syrigos KN. Sunitinib: a multitargeted receptor tyrosine kinase inhibitor in the era of molecular cancer therapies. BioDrugs. 2009;23(6):377–89.

    CAS  PubMed  Google Scholar 

  122. Dubois SG, Shusterman S, Ingle AM, et al. Phase I and pharmacokinetic study of sunitinib in pediatric patients with refractory solid tumors: a children’s oncology group study. Clin Cancer Res. 2011;17(15):5113–22.

    CAS  PubMed  Google Scholar 

  123. Benesch M, Windelberg M, Sauseng W, et al. Compassionate use of bevacizumab (Avastin) in children and young adults with refractory or recurrent solid tumors. Ann Oncol. 2008;19(4):807–13.

    CAS  PubMed  Google Scholar 

  124. Ferrara N, Hillan KJ, Gerber HP, Novotny W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov. 2004;3(5):391–400.

    CAS  PubMed  Google Scholar 

  125. Holash J, Davis S, Papadopoulos N, et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci USA. 2002;99(17):11393–8.

    CAS  PubMed  Google Scholar 

  126. Glade Bender JL, Adamson PC, Reid JM, et al. Phase I trial and pharmacokinetic study of bevacizumab in pediatric patients with refractory solid tumors: a Children’s Oncology Group Study. J Clin Oncol. 2008;26(3):399–405.

    PubMed  Google Scholar 

  127. Leavey PJ, Mascarenhas L, Granowetter L, et al. Feasibility of bevacizumab (NSC 704865, BB-IND no. 7921) combined with vincristine, topotecan, and cyclophosphamide in patients with first recurrent Ewing sarcoma (EWS): a Children’s Oncology Group (COG) study [American Society of Clinical Oncology meeting abstract]. J Clin Oncol. 2010;28(15 Suppl):9552.

    Google Scholar 

  128. Park JR, Hawkins DS, Ingle M, Borinstein SC, Glade Bender JL, Yamashiro D, et al. A pediatric phase I trial and pharmacokinetic study of aflibercept (VEGF Trap): a COG phase I consortium study [American Society of Clinical Oncology meeting abstract]. J Clin Oncol. 2010;28(15):9530.

    Google Scholar 

  129. Wedge SR, Kendrew J, Hennequin LF, et al. AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Cancer Res. 2005;65(10):4389–400.

    CAS  PubMed  Google Scholar 

  130. Gardner K, Judson I, Leahy M, et al. Activity of cediranib, a highly potent and selective VEGF signalling inhibitor, in alveolar soft part sarcoma [American Society of Clinical Oncology meeting abstract]. J Clin Oncol. 2009;27(15Suppl):10523A.

    Google Scholar 

  131. Morton CL, Maris JM, Keir ST, et al. Combination testing of cediranib (AZD2171) against childhood cancer models by the pediatric preclinical testing program. Pediatr Blood Cancer. 2012;58(4):566–71.

    PubMed  Google Scholar 

  132. Fox E, Aplenc R, Bagatell R, et al. A phase 1 trial and pharmacokinetic study of cediranib, an orally bioavailable pan-vascular endothelial growth factor receptor inhibitor, in children and adolescents with refractory solid tumors. J Clin Oncol. 2010;28(35):5174–81.

    CAS  PubMed  Google Scholar 

  133. Engelman JA, Settleman J. Acquired resistance to tyrosine kinase inhibitors during cancer therapy. Curr Opin Genet Dev. 2008;18(1):73–9.

    CAS  PubMed  Google Scholar 

  134. Rosenzweig SA. Acquired resistance to drugs targeting receptor tyrosine kinases. Biochem Pharmacol. 2012;83(8):1041–8.

    CAS  PubMed  Google Scholar 

  135. Rexer BN, Engelman JA, Arteaga CL. Overcoming resistance to tyrosine kinase inhibitors: lessons learned from cancer cells treated with EGFR antagonists. Cell Cycle. 2009;8(1):18–22.

    CAS  PubMed  Google Scholar 

  136. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012;149(2):274–93.

    CAS  PubMed  Google Scholar 

  137. Mateo-Lozano S, Tirado OM, Notario V. Rapamycin induces the fusion-type independent downregulation of the EWS/FLI-1 proteins and inhibits Ewing’s sarcoma cell proliferation. Oncogene. 2003;22(58):9282–7.

    CAS  PubMed  Google Scholar 

  138. Spunt SL, Grupp SA, Vik TA, et al. Phase I study of temsirolimus in pediatric patients with recurrent/refractory solid tumors. J Clin Oncol. 2011;29(21):2933–40.

    CAS  PubMed  Google Scholar 

  139. Mita MM, Mita AC, Chu QS, et al. Phase I trial of the novel mammalian target of rapamycin inhibitor deforolimus (AP23573; MK-8669) administered intravenously daily for 5 days every 2 weeks to patients with advanced malignancies. J Clin Oncol. 2008;26(3):361–7.

    CAS  PubMed  Google Scholar 

  140. Chawla SP, Staddon AP, Baker LH, et al. Phase II study of the mammalian target of rapamycin inhibitor ridaforolimus in patients with advanced bone and soft tissue sarcomas. J Clin Oncol. 2012;30(1):78–84.

    CAS  PubMed  Google Scholar 

  141. Temsirolimus, irinotecan hydrochoride, and temozolomide in treating young patients with relapsed or refractory solid tumors (ADVL0918) [NCT01141244]. http://www.clinicaltrials/gov/ct2/show/NCT01141244 (Accessed 10 Jul 2012).

  142. Sachdev D, Yee D. Disrupting insulin-like growth factor signaling as a potential cancer therapy. Mol Cancer Ther. 2007;6(1):1–12.

    CAS  PubMed  Google Scholar 

  143. Scotlandi K, Picci P. Targeting insulin-like growth factor 1 receptor in sarcomas. Curr Opin Oncol. 2008;20(4):419–27.

    CAS  PubMed  Google Scholar 

  144. Pollak M. The insulin and insulin-like growth factor receptor family in neoplasia: an update. Nat Rev Cancer. 2012;12(3):159–69.

    CAS  PubMed  Google Scholar 

  145. Sheppard K, Kinross KM, Solomon B, Pearson RB, Phillips WA. Targeting PI3 kinase/AKT/mTOR signaling in cancer. Crit Rev Oncog. 2012;17(1):69–95.

    PubMed  Google Scholar 

  146. Kim SY, Toretsky JA, Scher D, Helman LJ. The role of IGF-1R in pediatric malignancies. Oncologist. 2009;14(1):83–91.

    CAS  PubMed  Google Scholar 

  147. Olmos D, Tan DS, Jones RL, Judson IR. Biological rationale and current clinical experience with anti-insulin-like growth factor 1 receptor monoclonal antibodies in treating sarcoma: twenty years from the bench to the bedside. Cancer J. 2010;16(3):183–94.

    CAS  PubMed  Google Scholar 

  148. Olmos D, Martins AS, Jones RL, Alam S, Scurr M, Judson IR. Targeting the insulin-like growth factor 1 receptor in Ewing’s sarcoma: reality and expectations. Sarcoma. 2011;2011:402508.

    PubMed  Google Scholar 

  149. Erkizan HV, Uversky VN, Toretsky JA. Oncogenic partnerships: EWS–FLI1 protein interactions initiate key pathways of Ewing’s sarcoma. Clin Cancer Res. 2010;16(16):4077–83.

    CAS  PubMed  Google Scholar 

  150. Prieur A, Tirode F, Cohen P, Delattre O. EWS/FLI-1 silencing and gene profiling of Ewing cells reveal downstream oncogenic pathways and a crucial role for repression of insulin-like growth factor binding protein 3. Mol Cell Biol. 2004;24(16):7275–83.

    CAS  PubMed  Google Scholar 

  151. Benini S, Zuntini M, Manara MC, et al. Insulin-like growth factor binding protein 3 as an anticancer molecule in Ewing’s sarcoma. Int J Cancer. 2006;119(5):1039–46.

    CAS  PubMed  Google Scholar 

  152. Valenciano A, Henriquez-Hernandez LA, Moreno M, Lloret M, Lara PC. Role of IGF-1 receptor in radiation response. Transl Oncol. 2012;5(1):1–9.

    PubMed  Google Scholar 

  153. Tognon CE, Sorensen PH. Targeting the insulin-like growth factor 1 receptor (IGF1R) signaling pathway for cancer therapy. Expert Opin Ther Targets. 2012;16(1):33–48.

    CAS  PubMed  Google Scholar 

  154. Borinstein SC, Barkauskas DA, Krailo M, et al. Investigation of the insulin-like growth factor-1 signaling pathway in localized Ewing sarcoma: a report from the Children’s Oncology Group. Cancer. 2011;117(21):4966–76.

    CAS  PubMed  Google Scholar 

  155. Gombos A, Metzger-Filho O, Dal Lago L, Awada-Hussein A. Clinical development of insulin-like growth factor receptor-1 (IGF-1R) inhibitors: at the crossroad? Invest New Drugs. 2012;30:2433–42.

    CAS  PubMed  Google Scholar 

  156. Kolb EA, Gorlick R, Maris JM, et al. Combination testing (stage 2) of the anti-IGF-1 receptor antibody IMC-A12 with rapamycin by the pediatric preclinical testing program. Pediatr Blood Cancer. 2012;58(5):729–35.

    PubMed  Google Scholar 

  157. Maki RG. Small is beautiful: insulin-like growth factors and their role in growth, development, and cancer. J Clin Oncol. 2010;28(33):4985–95.

    CAS  PubMed  Google Scholar 

  158. Kolb EA, Gorlick R, Houghton PJ, et al. Initial testing (stage 1) of a monoclonal antibody (SCH 717454) against the IGF-1 receptor by the pediatric preclinical testing program. Pediatr Blood Cancer. 2008;50(6):1190–7.

    PubMed  Google Scholar 

  159. Houghton PJ, Morton CL, Gorlick R, et al. Initial testing of a monoclonal antibody (IMC-A12) against IGF-1R by the Pediatric Preclinical Testing Program. Pediatr Blood Cancer. 2010;54(7):921–6.

    PubMed  Google Scholar 

  160. Tolcher AW, Sarantopoulos J, Patnaik A, et al. Phase I, pharmacokinetic, and pharmacodynamic study of AMG 479, a fully human monoclonal antibody to insulin-like growth factor receptor 1. J Clin Oncol. 2009;27(34):5800–7.

    CAS  PubMed  Google Scholar 

  161. Juergens H, Daw NC, Geoerger B, et al. Preliminary efficacy of the anti-insulin-like growth factor type 1 receptor antibody figitumumab in patients with refractory Ewing sarcoma. J Clin Oncol. 2011;29(34):4534–40.

    CAS  PubMed  Google Scholar 

  162. Pappo AS, Patel SR, Crowley J, et al. R1507, a monoclonal antibody to the insulin-like growth factor 1 receptor, in patients with recurrent or refractory Ewing sarcoma family of tumors: results of a phase II Sarcoma Alliance for Research through Collaboration study. J Clin Oncol. 2011;29(34):4541–7.

    CAS  PubMed  Google Scholar 

  163. Tap WD, Demetri G, Barnette P, et al. Phase II study of ganitumab, a fully human anti-type-1 insulin-like growth factor receptor antibody, in patients with metastatic Ewing family tumors or desmoplastic small round cell tumors. J Clin Oncol. 2012;30(15):1849–56.

    CAS  PubMed  Google Scholar 

  164. Gualberto A, Pollak M. Clinical development of inhibitors of the insulin-like growth factor receptor in oncology. Curr Drug Targets. 2009;10(10):923–36.

    CAS  PubMed  Google Scholar 

  165. Garofalo C, Manara MC, Nicoletti G, et al. Efficacy of and resistance to anti-IGF-1R therapies in Ewing’s sarcoma is dependent on insulin receptor signaling. Oncogene. 2011;30(24):2730–40.

    CAS  PubMed  Google Scholar 

  166. Huang F, Hurlburt W, Greer A, et al. Differential mechanisms of acquired resistance to insulin-like growth factor-i receptor antibody therapy or to a small-molecule inhibitor, BMS-754807, in a human rhabdomyosarcoma model. Cancer Res. 2010;70(18):7221–31.

    CAS  PubMed  Google Scholar 

  167. Ho AL, Schwartz GK. Targeting of insulin-like growth factor type 1 receptor in Ewing sarcoma: unfulfilled promise or a promising beginning? J Clin Oncol. 2011;29(34):4581–3.

    CAS  PubMed  Google Scholar 

  168. Asmane I, Watkin E, Alberti L, et al. Insulin-like growth factor type 1 receptor (IGF-1R) exclusive nuclear staining: a predictive biomarker for IGF-1R monoclonal antibody (Ab) therapy in sarcomas. Eur J Cancer. 2012;48(16):3027–35.

    CAS  PubMed  Google Scholar 

  169. Gong Y, Yao E, Shen R, et al. High expression levels of total IGF-1R and sensitivity of NSCLC cells in vitro to an anti-IGF-1R antibody (R1507). PLoS One. 2009;4(10):e7273.

    PubMed  Google Scholar 

  170. Zha J, Lackner MR. Targeting the insulin-like growth factor receptor-1R pathway for cancer therapy. Clin Cancer Res. 2010;16(9):2512–7.

    CAS  PubMed  Google Scholar 

  171. Villanueva J, Vultur A, Lee JT, et al. Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by co-targeting MEK and IGF-1R/PI3K. Cancer Cell. 2010;18(6):683–95.

    CAS  PubMed  Google Scholar 

  172. Chandarlapaty S, Sawai A, Scaltriti M, et al. AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell. 2011;19(1):58–71.

    CAS  PubMed  Google Scholar 

  173. Wan X, Harkavy B, Shen N, Grohar P, Helman LJ. Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism. Oncogene. 2007;26(13):1932–40.

    CAS  PubMed  Google Scholar 

  174. Naing A, LoRusso P, Fu S, et al. Insulin growth factor-receptor (IGF-1R) antibody cixutumumab combined with the mTOR inhibitor temsirolimus in patients with refractory Ewing’s sarcoma family tumors. Clin Cancer Res. 2012;18(9):2625–31.

    CAS  PubMed  Google Scholar 

  175. Schwartz G, Tap WD, Qin LX, Livingston MB, Undevia SD, Chmielowski B, et al. A phase II multicenter study of the IGF-1 receptor antibody cixutumumab (A12) and the mTOR inhibitor temsirolimus (TEM) in patients (pts) with refractory IGF-1R positive (+) and negative (−) bone and soft tissue sarcomas (STS) [American Society of Clinical Oncology meeting abstract]. J Clin Oncol. 2012;29(10 Suppl):10003.

    Google Scholar 

  176. Dong J, Demarest SJ, Sereno A, et al. Combination of two insulin-like growth factor-I receptor inhibitory antibodies targeting distinct epitopes leads to an enhanced antitumor response. Mol Cancer Ther. 2010;9(9):2593–604.

    CAS  PubMed  Google Scholar 

  177. Mulvihill MJ, Cooke A, Rosenfeld-Franklin M, et al. Discovery of OSI-906: a selective and orally efficacious dual inhibitor of the IGF-1 receptor and insulin receptor. Future Med Chem. 2009;1(6):1153–71.

    CAS  PubMed  Google Scholar 

  178. Buck E, Gokhale PC, Koujak S, et al. Compensatory insulin receptor (IR) activation on inhibition of insulin-like growth factor-1 receptor (IGF-1R): rationale for cotargeting IGF-1R and IR in cancer. Mol Cancer Ther. 2010;9(10):2652–64.

    CAS  PubMed  Google Scholar 

  179. Blackburn EH. Structure and function of telomeres. Nature. 1991;350(6319):569–73.

    CAS  PubMed  Google Scholar 

  180. Tabori U, Dome JS. Telomere biology of pediatric cancer. Cancer Invest. 2007;25(3):197–208.

    CAS  PubMed  Google Scholar 

  181. Proctor A, Brownhill SC, Burchill SA. The promise of telomere length, telomerase activity and its regulation in the translocation-dependent cancer ESFT; clinical challenges and utility. Biochim Biophys Acta. 2009;1792(4):260–74.

    CAS  PubMed  Google Scholar 

  182. Avigad S, Naumov I, Ohali A, et al. Short telomeres: a novel potential predictor of relapse in Ewing sarcoma. Clin Cancer Res. 2007;13(19):5777–83.

    CAS  PubMed  Google Scholar 

  183. Boro A, Pretre K, Rechfeld F, et al. Small-molecule screen identifies modulators of EWS/FLI1 target gene expression and cell survival in Ewing’s sarcoma. Int J Cancer. 2012;131(9):2153–64.

    CAS  PubMed  Google Scholar 

  184. Hofbauer S, Hamilton G, Theyer G, Wollmann K, Gabor F. Insulin-like growth factor-I-dependent growth and in vitro chemosensitivity of Ewing’s sarcoma and peripheral primitive neuroectodermal tumour cell lines. Eur J Cancer. 1993;29A(2):241–5.

    CAS  PubMed  Google Scholar 

  185. Stegmaier K, Wong JS, Ross KN, et al. Signature-based small molecule screening identifies cytosine arabinoside as an EWS/FLI modulator in Ewing sarcoma. PLoS Med. 2007;4(4):e122.

    PubMed  Google Scholar 

  186. DuBois SG, Krailo MD, Lessnick SL, et al. Phase II study of intermediate-dose cytarabine in patients with relapsed or refractory Ewing sarcoma: a report from the Children’s Oncology Group. Pediatr Blood Cancer. 2009;52(3):324–7.

    PubMed  Google Scholar 

  187. Grohar PJ, Woldemichael GM, Griffin LB, et al. Identification of an inhibitor of the EWS–FLI1 oncogenic transcription factor by high-throughput screening. J Natl Cancer Inst. 2011;103(12):962–78.

    CAS  PubMed  Google Scholar 

  188. Yu AL, Gilman AL, Ozkaynak MF, et al. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med. 2010;363(14):1324–34.

    CAS  PubMed  Google Scholar 

  189. Scotlandi K, Baldini N, Cerisano V, et al. CD99 engagement: an effective therapeutic strategy for Ewing tumors. Cancer Res. 2000;60(18):5134–42.

    CAS  PubMed  Google Scholar 

  190. Rocchi A, Manara MC, Sciandra M, et al. CD99 inhibits neural differentiation of human Ewing sarcoma cells and thereby contributes to oncogenesis. J Clin Invest. 2010;120(3):668–80.

    CAS  PubMed  Google Scholar 

  191. Franzetti GA, Laud-Duval K, Bellanger D, Stern MH, Sastre-Garau X, Delattre O. MiR-30a-5p connects EWS–FLI1 and CD99, two major therapeutic targets in Ewing tumor. Oncogene. 2012;. doi:10.1038/onc.2012.403.

    Google Scholar 

  192. Cerisano V, Aalto Y, Perdichizzi S, et al. Molecular mechanisms of CD99-induced caspase-independent cell death and cell–cell adhesion in Ewing’s sarcoma cells: actin and zyxin as key intracellular mediators. Oncogene. 2004;23(33):5664–74.

    CAS  PubMed  Google Scholar 

  193. Scotlandi K, Perdichizzi S, Bernard G, et al. Targeting CD99 in association with doxorubicin: an effective combined treatment for Ewing’s sarcoma. Eur J Cancer. 2006;42(1):91–6.

    CAS  PubMed  Google Scholar 

  194. Gellini M, Ascione A, Flego M, et al. Generation of human single-chain antibody to the CD99 cell surface determinant specifically recognizing Ewing’s sarcoma tumor cells. Curr Pharm Biotechnol. 2012 (Epub ahead of print).

  195. Green JR. Bisphosphonates: preclinical review. Oncologist. 2004;9(Suppl 4):3–13.

    CAS  PubMed  Google Scholar 

  196. Wong MH, Stockler MR, Pavlakis N. Bisphosphonates and other bone agents for breast cancer. Cochrane Database Syst Rev. 2012;(2):CD003474.

  197. Sonnemann J, Eckervogt V, Truckenbrod B, Boos J, Winkelmann W, van Valen F. The bisphosphonate pamidronate is a potent inhibitor of Ewing’s sarcoma cell growth in vitro. Anticancer Drugs. 2003;14(9):767–71.

    CAS  PubMed  Google Scholar 

  198. Kubo T, Shimose S, Matsuo T, et al. Inhibitory effects of a new bisphosphonate, minodronate, on proliferation and invasion of a variety of malignant bone tumor cells. J Orthop Res. 2006;24(6):1138–44.

    CAS  PubMed  Google Scholar 

  199. Study in localized and disseminated Ewing sarcoma (EWING 2008) [NCT 00987636]. http://www.clinicaltrials.gov/ct2/show/NCT00987636 (Accessed 10 Jul 2012).

  200. Burchill SA, Berry PA, Bradbury FM, Lewis IJ. Contrasting levels of p21ras activation and expression of neurofibromin in peripheral primitive neuroectodermal tumour and neuroblastoma cells, and their response to retinoic acid. J Neurol Sci. 1998;157(2):129–37.

    CAS  PubMed  Google Scholar 

  201. Batra S, Reynolds CP, Maurer BJ. Fenretinide cytotoxicity for Ewing’s sarcoma and primitive neuroectodermal tumor cell lines is decreased by hypoxia and synergistically enhanced by ceramide modulators. Cancer Res. 2004;64(15):5415–24.

    CAS  PubMed  Google Scholar 

  202. Myatt SS, Burchill SA. The sensitivity of the Ewing’s sarcoma family of tumours to fenretinide-induced cell death is increased by EWS–Fli1-dependent modulation of p38(MAPK) activity. Oncogene. 2008;27(7):985–96.

    CAS  PubMed  Google Scholar 

  203. Villablanca JG, Krailo MD, Ames MM, Reid JM, Reaman GH, Reynolds CP. Phase I trial of oral fenretinide in children with high-risk solid tumors: a report from the Children’s Oncology Group (CCG 09709). J Clin Oncol. 2006;24(21):3423–30.

    CAS  PubMed  Google Scholar 

  204. Suva ML, Riggi N, Stehle JC, et al. Identification of cancer stem cells in Ewing’s sarcoma. Cancer Res. 2009;69(5):1776–81.

    CAS  PubMed  Google Scholar 

  205. Leacock SW, Basse AN, Chandler GL, Kirk AM, Rakheja D, Amatruda JF. A zebrafish transgenic model of Ewing’s sarcoma reveals conserved mediators of EWS–FLI1 tumorigenesis. Dis Model Mech. 2012;5(1):95–106.

    CAS  PubMed  Google Scholar 

  206. Honoki K. Do stem-like cells play a role in drug resistance of sarcomas? Expert Rev Anticancer Ther. 2010;10(2):261–70.

    CAS  PubMed  Google Scholar 

  207. Trucco M, Loeb D. Sarcoma stem cells: do we know what we are looking for? Sarcoma. 2012;2012:291705.

    PubMed  Google Scholar 

  208. Jiang X, Gwye Y, Russell D, et al. CD133 expression in chemo-resistant Ewing sarcoma cells. BMC Cancer. 2010;10:116.

    PubMed  Google Scholar 

  209. Hirschmann-Jax C, Foster AE, Wulf GG, et al. A distinct “side population” of cells with high drug efflux capacity in human tumor cells. Proc Natl Acad Sci USA. 2004;101(39):14228–33.

    CAS  PubMed  Google Scholar 

  210. Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer. 2005;5(4):275–84.

    CAS  PubMed  Google Scholar 

  211. Mimeault M, Hauke R, Batra SK. Recent advances on the molecular mechanisms involved in the drug resistance of cancer cells and novel targeting therapies. Clin Pharmacol Ther. 2008;83(5):673–91.

    CAS  PubMed  Google Scholar 

  212. Townsend DM, Tew KD. The role of glutathione-S-transferase in anti-cancer drug resistance. Oncogene. 2003;22(47):7369–75.

    CAS  PubMed  Google Scholar 

  213. Besancon R, Valsesia-Wittmann S, Puisieux A, Caron de Fromentel C, Maguer-Satta V. Cancer stem cells: the emerging challenge of drug targeting. Curr Med Chem. 2009;16(4):394–416.

    CAS  PubMed  Google Scholar 

  214. Scotlandi K, Remondini D, Castellani G, et al. Overcoming resistance to conventional drugs in Ewing sarcoma and identification of molecular predictors of outcome. J Clin Oncol. 2009;27(13):2209–16.

    CAS  PubMed  Google Scholar 

  215. Kovar H, Alonso J, Aman P, et al. The first European interdisciplinary Ewing sarcoma research summit. Front Oncol. 2012;2:54.

    PubMed  Google Scholar 

  216. Burgert EO Jr, Nesbit ME, Garnsey LA, et al. Multimodal therapy for the management of nonpelvic, localized Ewing’s sarcoma of bone: Intergroup study IESS-II. J Clin Oncol. 1990;8(9):1514–24.

    PubMed  Google Scholar 

  217. Paulussen M, Craft AW, Lewis I, et al. Results of the EICESS-92 Study: two randomized trials of Ewing’s sarcoma treatment—cyclophosphamide compared with ifosfamide in standard-risk patients and assessment of benefit of etoposide added to standard treatment in high-risk patients. J Clin Oncol. 2008;26(27):4385–93.

    CAS  PubMed  Google Scholar 

  218. Rosen G, Caparros B, Mosende C, McCormick B, Huvos AG, Marcove RC. Curability of Ewing’s sarcoma and considerations for future therapeutic trials. Cancer. 1978;41(3):888–99.

    CAS  PubMed  Google Scholar 

  219. Hayes FA, Thompson EI, Meyer WH, et al. Therapy for localized Ewing’s sarcoma of bone. J Clin Oncol. 1989;7(2):208–13.

    CAS  PubMed  Google Scholar 

  220. Jurgens H, Exner U, Gadner H, et al. Multidisciplinary treatment of primary Ewing’s sarcoma of bone: a 6-year experience of a European Cooperative Trial. Cancer. 1988;61(1):23–32.

    CAS  PubMed  Google Scholar 

  221. Craft A, Cotterill S, Malcolm A, et al. Ifosfamide-containing chemotherapy in Ewing’s sarcoma: the Second United Kingdom Children’s Cancer Study Group and the Medical Research Council Ewing’s Tumor Study. J Clin Oncol. 1998;16(11):3628–33.

    CAS  PubMed  Google Scholar 

  222. Bacci G, Mercuri M, Longhi A, et al. Neoadjuvant chemotherapy for Ewing’s tumour of bone: recent experience at the Rizzoli Orthopaedic Institute. Eur J Cancer. 2002;38(17):2243–51.

    CAS  PubMed  Google Scholar 

  223. Kolb EA, Kushner BH, Gorlick R, et al. Long-term event-free survival after intensive chemotherapy for Ewing’s family of tumors in children and young adults. J Clin Oncol. 2003;21(18):3423–30.

    CAS  PubMed  Google Scholar 

  224. Minard-Colin V, Ichante JL, Nguyen L, et al. Phase II study of vinorelbine and continuous low doses cyclophosphamide in children and young adults with a relapsed or refractory malignant solid tumour: good tolerance profile and efficacy in rhabdomyosarcoma - a report from the Societe Francaise des Cancers et leucemies de l’Enfant et de l’adolescent (SFCE). Eur J Cancer. 2012;45(15):2409–16.

    Google Scholar 

  225. Widemann BC, Kim A, Fox E, et al. A phase I trial and pharmacokinetic study of sorafenib in children with refractory solid tumors or leukemias: a Children’s Oncology Group Phase I Consortium Report. Clin Cancer Res. 2012;18(21):6021–2.

    Google Scholar 

  226. Malempati S, Weigel B, Ingle AM, et al. Phase I/II trial and pharmacokinetic study of cixutumumab in pediatric patients with refractory solid tumors and Ewing sarcoma: a report from the Children’s Oncology Group. J Clin Oncol. 2012;30(3):256–62.

    CAS  PubMed  Google Scholar 

  227. Imetelstat sodium in treating young patients with refractory or recurrent solid tumors or lymphoma. (COG ADVL1112 [NCT01273090]). http://www.clinicaltrials.gov/ct2/show/NCT0273090 (Accessed 30 Nov 2012).

  228. Mithramycin for children and adults with solid tumors or Ewing sarcoma. [NCT01610570]. http://www.clinicaltrials.gov/ct2/show/NCT01610570 (Accessed 30 Nov 2012).

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  1. The Division of Hematology/Oncology, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, ON, M5G 1N6, Canada

    Cormac Owens, Lesleigh S. Abbott & Abha A. Gupta

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  3. Abha A. Gupta
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Correspondence to Cormac Owens.

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Owens, C., Abbott, L.S. & Gupta, A.A. Optimal Management of Ewing Sarcoma Family of Tumors: Recent Developments in Systemic Therapy. Pediatr Drugs 15, 473–492 (2013). https://doi.org/10.1007/s40272-013-0037-1

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