Abstract
Ewing’s sarcoma family of tumors (ESFT) is a malignant tumor of bone and soft tissue in children and adolescents that is characterized by molecular alterations that most commonly involve the EWS gene on chromosome 22. It is an aggressive tumor, with metastases present at diagnosis in 20–25% of cases. Modern treatment regimens for localized disease have resulted in significant improvement in survival. However, the presence of metastasis is associated with mortality in 70–80% of patients. New insights into the pathogenesis and proliferative mechanisms of human cancers have led to the identification of a number of proteins acting as messenger molecules and modulators of tumor growth. Targeting these molecules in ESFT has the potential effect of controlling tumor growth. This chapter summarizes the current research on molecular pathogenesis, proliferation pathways and new investigational pharmacologic agents that are under development in the race for the cure of this malignancy.
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References
Ahmed AA, Sherman AK, Pawel BR (2011) Expression of therapeutic targets in Ewing sarcoma family tumors. Hum Pathol 43(7):1077–1083
Applebaum MA, Worch J, Matthay KK, Goldsby R, Neuhaus J, West DC, DuBois SG (2011) Clinical features and outcomes in patients with extraskeletal Ewing sarcoma. Cancer 117:3027–3032
Arvand A, Denny CT (2001) Biology of EWS/ETS fusions in Ewing’s family tumors. Oncogene 20:5747–5754
Bacci G, Balladelli A, Forni C, Longhi A, Serra M, Fabbri N, Alberghini M, Ferrari S, Benassi MS, Picci P (2007) Ewing’s sarcoma family tumours. Differences in clinicopathological characteristics at presentation between localised and metastatic tumours. J Bone Joint Surg Br 89:1229–1233
Bernstein M, Kovar H, Paulussen M, Randall RL, Schuck A, Teot LA, Juergens H (2006) Ewing’s sarcoma family of tumors: current management. Oncologist 11:503–519
Bjornsti MA, Houghton PJ (2004) The TOR pathway: a target for cancer therapy. Nat Rev Cancer 4:335–348
Brenner JC, Feng FY, Han S, Patel S, Goyal SV, Bou-Maroun LM, Liu M, Lonigro R, Prensner JR, Tomlins SA, Chinnaiyan AM (2012) PARP-1 inhibition as a targeted strategy to treat Ewing’s sarcoma. Cancer Res 72:1608–1613
Bozzi F, Tamborini E, Negri T, Pastore E, Ferrari A, Luksch R, Casanova M, Pierotti MA, Bellani FF, Pilotti S (2007) Evidence for activation of KIT, PDGFRa, and PDGFRb receptors in the Ewing sarcoma family of tumors. Cancer 109:1638–1645
Dalal S, Berry AM, Cullinane CJ, Mangham DC, Grimer R, Lewis IJ, Johnston C, Laurence V, Burchill SA (2005) Vascular endothelial growth factor: a therapeutic target for tumors of the Ewing’s sarcoma family. Clin Cancer Res 11:2364–2378
De Vito C, Riggi N, Suva ML, Janiszewska M, Horlbeck J, Baumer K, Provero P, Stamenkovic I (2011) Let-7a is a direct EWS-FLI-1 target implicated in Ewing’s sarcoma development. PLoS One 6:e23592
Erkizan HV, Kong Y, Merchant M, Schlottmann S, Barber-Rotenberg JS, Yuan L, Abaan OD, Chou TH, Dakshanamurthy S, Brown ML, Uren A, Toretsky JA (2009) A small molecule blocking oncogenic protein EWS-FLI1 interaction with RNA helicase A inhibits growth of Ewing’s sarcoma. Nat Med 15:750–756
Faivre S, Kroemer G, Raymond E (2006) Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov 5:671–688
Giovannini M, Biegel JA, Serra M, Wang JY, Wei YH, Nycum L, Emanuel BS, Evans GA (1994) EWS-erg and EWS-FLI1 fusion transcripts in Ewing’s sarcoma and primitive neuroectodermal tumor with variant translocations. J Clin Invest 94:489–496
Girnita L, Girnita A, Wang M, Meis-Kindblom JM, Kindblom LG, Larsso O (2000) A link between basic fibroblast growth factor (bFGF) and EWS/FLI-1 in Ewing’s sarcoma cells. Oncogene 19:4298–4301
Grimberg A, Cohen P (2000) Role of insulin-like growth factors and their binding proteins in growth control and carcinogenesis. J Cell Physiol 183:1–9
Guba M, von Breitenbuch P, Steinbauer M, Koehl G, Flegel S, Hornung M, Bruns CJ, Zuelke C, Farkas S, Anthuber M, Jauch KW, Geissler EK (2002) Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med 8:128–135
Herrero-Martin D, Fourtouna A, Niedan S, Riedmann LT, Schwentner R, Arvee DN (2011) Factors affecting EWS-FLI1 activity in Ewing’s sarcoma. Sarcoma 2011:352580
Ho AL, Schwartz GK (2011) Targeting of insulin-like growth factor type 1 receptor in Ewing sarcoma: unfulfilled promise or a promising beginning? J Clin Oncol 29:4581–4583
Jedlicka P (2010) Ewing Sarcoma, an enigmatic malignancy of likely progenitor cell origin, driven by transcription factor oncogenic fusions. Int J Clin Exp Pathol 3:338–347
Ladenstein R, Potschger U, Le Deley MC, Whelan J, Paulussen M, Oberlin O, Van den Berg H, Dirksen U, Hjorth L, Michon J, Lewis I, Craft A, Jürgens H (2010) Primary disseminated multifocal Ewing sarcoma: results of the Euro-EWING 99 trial. J Clin Oncol 28:3284–3291
Lewis TB, Coffin CM, Bernard PS (2007) Differentiating Ewing’s sarcoma from other round blue cell tumors using a RT-PCR translocation panel on formalin-fixed paraffin-embedded tissues. Mod Pathol 20:397–404
Lin PP, Wang Y, Lozano G (2011) Mesenchymal stem cells and the origin of Ewing’s sarcoma. Sarcoma 2011:2011
Mateo-Lozano S, Tirado OM, Notario V (2003) Rapamycin induces the fusion-type independent downregulation of the EWS/FLI-1 proteins and inhibits Ewing’s sarcoma cell proliferation. Oncogene 22:9282–9287
McAllister NR, Lessnick SL (2005) The potential for molecular therapeutic targets in Ewing’s sarcoma. Curr Treat Options Oncol 6:461–471
Miyagawa Y, Okita H, Nakaijima H, Horiuchi Y, Sato B, Taguchi T, Toyoda M, Katagiri YU, Fujimoto J, Hata J, Umezawa A, Kiyokawa N (2008) Inducible expression of chimeric EWS/ETS proteins confers Ewing’s family tumor-like phenotypes to human mesenchymal progenitor cells. Mol Cell Biol 28:2125–2137
Nagano A, Ohno T, Shimizu K, Hara A, Yamamoto T, Kawai G, Saitou M, Takiqami I, Matsuhashi A, Yamada K, Takei Y (2010) EWS/Fli-1 chimeric fusion gene upregulates vascular endothelial growth factor-A. Int J Cancer 126:2790–2798
Paulussen M, Fröhlich B, Jürgens H (2001) Ewing tumour incidence, prognosis and treatment options. Paediatr Drugs 3:899–913
Pinto A, Dickman P, Parham D (2011) Pathobiologic markers of the Ewing sarcoma family of tumors: state of the art and prediction of behaviour. Sarcoma 2011:856190
Riggi N, Cironi L, Provero P, Suva ML, Kaloulis K, Garcia-Echeverria C, Hoffmann F, Trumpp A, Stamenkovic I (2005) Development of Ewing’s sarcoma from primary bone marrow–derived mesenchymal progenitor cells. Cancer Res 65:11459–11468
Riggi N, Suva ML, Suva D, Cironi L, Provero P, Tercier S, Joseph JM, Stehle JC, Baumer K, Kindler V, Stamenkovic I (2008) EWS-FLI-1 expression triggers a Ewing’s sarcoma initiation program in primary human mesenchymal stem cells. Cancer Res 68:2176–2185
Rocchi A, Manara MC, Sciandra M, Zambelli D, Filippo Nardi F, Nicoletti G, Garofalo C, Meschini S, Astolfi A (2010) CD99 inhibits neural differentiation of human Ewing sarcoma cells and thereby contributes to oncogenesis. J Clin Invest 120:668–680
Scotlandi K, Benini S, Sarti M, Serra M, Loffini PL, Maurici D, Picci N, Manara MC, BaIdini N (1996) Insulin-like growth factor I receptor-mediated circuit in Ewing’s sarcoma/peripheral neuroectodermal tumor: a possible therapeutic target. Cancer Res 56:4570–4574
Scotlandi K, Manara MC, Nicoletti G, Lollini PL, Lukas S, Benini S, Croci S, Perdichizzi S, Zambelli D, Serra M, García-Echeverría C, Hofmann F, Picci P (2005) Antitumor activity of the insulin-like growth factor-I receptor kinase inhibitor NVP-AEW541 in musculoskeletal tumors. Cancer Res 65:3868–3876
Stewart KS, Kleinerman ES (2011) Tumor vessel development and expansion in Ewing’s sarcoma: a review of the vasculogenesis process and clinical trials with vascular targeting agents. Sarcoma 2011:165837
Subbiah V, Anderson P (2011) Targeted therapy of Ewing’s sarcoma. Sarcoma 2011:686985
Toomey EC, Schiffman JD, Lessnick SL (2010) Recent advances in the molecular pathogenesis of Ewing’s sarcoma. Oncogene 29:4504–4516
Toretsky JA, Kalebic T, Blakesley V, LeRoith D, Helman LJ (1997) The insulin-like growth factor-I receptor is required for EWS/FLI-1 transformation of fibroblasts. J Biol Chem 272:30822–30827
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Ahmed, A.A., Samuel, G., Fulbright, J.M. (2013). Ewing’s Sarcoma Family of Tumors: Targeting Molecular Pathways and the Race for a Cure. In: Hayat, M. (eds) Pediatric Cancer, Volume 4. Pediatric Cancer, vol 4. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-6591-7_21
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DOI: https://doi.org/10.1007/978-94-007-6591-7_21
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