Enhancer of zeste homolog 2 (EZH2) in pediatric soft tissue sarcomas: first implications

BMC Medicine

Rossella Rota²  Franco Locatelli⁴  Antonio Giordano¹  Lucio Miele³  Roberta Ciarapica² 

[1]Department of Human Pathology and Oncology, Università of Siena, Siena, Italy

[2]Department of Oncohematology, IRCCS, Ospedale Pediatrico Bambino Gesù, Roma, Italy

[3]Cancer Institute, University of Mississippi Medical Center, Jackson, MI, USA

[4]Dipartimento di Scienze Pediatriche, Università di Pavia, Pavia, Italy

关键词: methyltransferases;    methylation;    epigenetics;    soft tissue sarcomas;    EZH2;   

Others  :  1127002
DOI  :  10.1186/1741-7015-9-63

 received in 2011-02-02, accepted in 2011-05-25,  发布年份 2011

【 摘 要 】

Soft tissue sarcomas of childhood are a group of heterogeneous tumors thought to be derived from mesenchymal stem cells. Surgical resection is effective only in about 50% of cases and resistance to conventional chemotherapy is often responsible for treatment failure. Therefore, investigations on novel therapeutic targets are of fundamental importance. Deregulation of epigenetic mechanisms underlying chromatin modifications during stem cell differentiation has been suggested to contribute to soft tissue sarcoma pathogenesis. One of the main elements in this scenario is enhancer of zeste homolog 2 (EZH2), a methyltransferase belonging to the Polycomb group proteins. EZH2 catalyzes histone H3 methylation on gene promoters, thus repressing genes that induce stem cell differentiation to maintain an embryonic stem cell signature. EZH2 deregulated expression/function in soft tissue sarcomas has been recently reported. In this review, an overview of the recently reported functions of EZH2 in soft tissue sarcomas is given and the hypothesis that its expression might be involved in soft tissue sarcomagenesis is discussed. Finally, the therapeutic potential of epigenetic therapies modulating EZH2-mediated gene repression is considered.

【 授权许可】

   
2011 Ciarapica et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 2.

【 参考文献 】

• [1]Siddiqi S, Mills J, Matushansky I: Epigenetic remodeling of chromatin architecture: exploring tumor differentiation therapies in mesenchymal stem cells and sarcomas. Curr Stem Cell Res Ther 2010, 5:63-73.
• [2]Jemal A, Siegel R, Xu J, Ward E: Cancer statistics, 2010. CA Cancer J Clin 2010, 60:277-300.
• [3]Vincenzi B, Frezza AM, Santini D, Tonini G: New therapies in soft tissue sarcoma. Expert Opin Emerg Drugs 2010, 15:237-248.
• [4]Ganjoo KN: New developments in targeted therapy for soft tissue sarcoma. Curr Oncol Rep 2010, 12:261-265.
• [5]Krikelis D, Judson I: Role of chemotherapy in the management of soft tissue sarcomas. Expert Rev Anticancer Ther 2010, 10:249-260.
• [6]Yoo CB, Jones PA: Epigenetic therapy of cancer: past, present and future. Nat Rev Drug Discov 2006, 5:37-50.
• [7]Simon JA, Lange CA: Roles of the EZH2 histone methyltransferase in cancer epigenetics. Mutat Res 2008, 647:21-29.
• [8]Sparmann A, van Lohuizen M: Polycomb silencers control cell fate, development and cancer. Nat Rev Cancer 2006, 6:846-856.
• [9]Ringrose L, Paro R: Epigenetic regulation of cellular memory by the Polycomb and Trithorax group proteins. Annu Rev Genet 2004, 38:413-443.
• [10]Rajasekhar VK, Begemann M: Concise review: roles of polycomb group proteins in development and disease: a stem cell perspective. Stem Cells 2007, 25:2498-2510.
• [11]Schuettengruber B, Chourrout D, Vervoort M, Leblanc B, Cavalli G: Genome regulation by polycomb and trithorax proteins. Cell 2007, 128:735-745.
• [12]Laible G, Wolf A, Dorn R, Reuter G, Nislow C, Lebersorger A, Popkin D, Pillus L, Jenuwein T: Mammalian homologues of the Polycomb-group gene Enhancer of zeste mediate gene silencing in Drosophila heterochromatin and at S. cerevisiae telomeres. Embo J 1997, 16:3219-3232.
• [13]Kleer CG, Cao Q, Varambally S, Shen R, Ota I, Tomlins SA, Ghosh D, Sewalt RG, Otte AP, Hayes DF, Sabel MS, Livant D, Weiss SJ, Rubin MA, Chinnaiyan AM: EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc Natl Acad Sci USA 2003, 100:11606-11611.
• [14]Varambally S, Dhanasekaran SM, Zhou M, Barrette TR, Kumar-Sinha C, Sanda MG, Ghosh D, Pienta KJ, Sewalt RG, Otte AP, Rubin MA, Chinnaiyan AM: The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 2002, 419:624-629.
• [15]Kuzmichev A, Margueron R, Vaquero A, Preissner TS, Scher M, Kirmizis A, Ouyang X, Brockdorff N, Abate-Shen C, Farnham P, Reinberg D: Composition and histone substrates of polycomb repressive group complexes change during cellular differentiation. Proc Natl Acad Sci USA 2005, 102:1859-1864.
• [16]Ciarapica R, Russo G, Verginelli F, Raimondi L, Donfrancesco A, Rota R, Giordano A: Deregulated expression of miR-26a and Ezh2 in rhabdomyosarcoma. Cell Cycle 2009, 8:172-175.
• [17]Richter GH, Plehm S, Fasan A, Rössler S, Unland R, Bennani-Baiti IM, Hotfilder M, Löwel D, von Luettichau I, Mossbrugger I, Quintanilla-Martinez L, Kovar H, Staege MS, Müller-Tidow C, Burdach S: EZH2 is a mediator of EWS/FLI1 driven tumor growth and metastasis blocking endothelial and neuro-ectodermal differentiation. Proc Natl Acad Sci USA 2009, 106:5324-5329.
• [18]De Giovanni C, Landuzzi L, Nicoletti G, Lollini PL, Nanni P: Molecular and cellular biology of rhabdomyosarcoma. Future Oncol 2009, 5:1449-1475.
• [19]Charytonowicz E, Cordon-Cardo C, Matushansky I, Ziman M: Alveolar rhabdomyosarcoma: is the cell of origin a mesenchymal stem cell? Cancer Lett 2009, 279:126-136.
• [20]Merlino G, Helman LJ: Rhabdomyosarcoma--working out the pathways. Oncogene 1999, 18:5340-5348.
• [21]Williamson D, Missiaglia E, de Reyniès A, Pierron G, Thuille B, Palenzuela G, Thway K, Orbach D, Laé M, Fréneaux P, Pritchard-Jones K, Oberlin O, Shipley J, Delattre O: Fusion gene-negative alveolar rhabdomyosarcoma is clinically and molecularly indistinguishable from embryonal rhabdomyosarcoma. J Clin Oncol 2010, 28:2151-2158.
• [22]Davicioni E, Anderson JR, Buckley JD, Meyer WH, Triche TJ: Gene expression profiling for survival prediction in pediatric rhabdomyosarcomas: a report from the children's oncology group. J Clin Oncol 2010, 28:1240-1246.
• [23]Davicioni E, Finckenstein FG, Shahbazian V, Buckley JD, Triche TJ, Anderson MJ: Identification of a PAX-FKHR gene expression signature that defines molecular classes and determines the prognosis of alveolar rhabdomyosarcomas. Cancer Res 2006, 66:6936-6946.
• [24]Lae M, Ahn EH, Mercado GE, Chuai S, Edgar M, Pawel BR, Olshen A, Barr FG, Ladanyi M: Global gene expression profiling of PAX-FKHR fusion-positive alveolar and PAX-FKHR fusion-negative embryonal rhabdomyosarcomas. J Pathol 2007, 212:143-151.
• [25]Wang H, Garzon R, Sun H, Ladner KJ, Singh R, Dahlman J, Cheng A, Hall BM, Qualman SJ, Chandler DS, Croce CM, Guttridge DC: NF-kappaB-YY1-miR-29 regulatory circuitry in skeletal myogenesis and rhabdomyosarcoma. Cancer Cell 2008, 14:369-381.
• [26]Ciarapica R, Pezzullo M, Verginelli F, Boldrini R, Sio LD, Stifani S, Giordano A, Rota R: Abstract #3417: Ezh2 is up-regulated and correlates with Ki67 and CD31 expression in human pediatric rhabdomyosarcoma. In AACR Meeting Abstracts. American Association for Cancer Reasearch, Philadelphia, PA; 2010.
• [27]Caretti G, Di Padova M, Micales B, Lyons GE, Sartorelli V: The Polycomb Ezh2 methyltransferase regulates muscle gene expression and skeletal muscle differentiation. Genes Dev 2004, 18:2627-2638.
• [28]Juan AH, Kumar RM, Marx JG, Young RA, Sartorelli V: Mir-214-dependent regulation of the polycomb protein Ezh2 in skeletal muscle and embryonic stem cells. Mol Cell 2009, 36:61-74.
• [29]Wong CF, Tellam RL: MicroRNA-26a targets the histone methyltransferase Enhancer of Zeste homolog 2 during myogenesis. J Biol Chem 2008, 283:9836-9843.
• [30]Wang H, Hertlein E, Bakkar N, Sun H, Acharyya S, Wang J, Carathers M, Davuluri R, Guttridge DC: NF-kappaB regulation of YY1 inhibits skeletal myogenesis through transcriptional silencing of myofibrillar genes. Mol Cell Biol 2007, 27:4374-4387.
• [31]Subramanian S, Lui WO, Lee CH, Espinosa I, Nielsen TO, Heinrich MC, Corless CL, Fire AZ, van de Rijn M: MicroRNA expression signature of human sarcomas. Oncogene 2008, 27:2015-2026.
• [32]Okcu MF, Despa S, Choroszy M, Berrak SG, Cangir A, Jaffe N, Raney RB: Synovial sarcoma in children and adolescents: thirty three years of experience with multimodal therapy. Med Pediatr Oncol 2001, 37:90-96.
• [33]Jain S, Xu R, Prieto VG, Lee P: Molecular classification of soft tissue sarcomas and its clinical applications. Int J Clin Exp Pathol 2010, 3:416-428.
• [34]Soulez M, Saurin AJ, Freemont PS, Knight JC: SSX and the synovial-sarcoma-specific chimaeric protein SYT-SSX co-localize with the human Polycomb group complex. Oncogene 1999, 18:2739-2746.
• [35]de Bruijn DR, Allander SV, van Dijk AH, Willemse MP, Thijssen J, van Groningen JJ, Meltzer PS, van Kessel AG: The synovial-sarcoma-associated SS18-SSX2 fusion protein induces epigenetic gene (de)regulation. Cancer Res 2006, 66:9474-9482.
• [36]Lubieniecka JM, de Bruijn DR, Su L, van Dijk AH, Subramanian S, van de Rijn M, Poulin N, van Kessel AG, Nielsen TO: Histone deacetylase inhibitors reverse SS18-SSX-mediated polycomb silencing of the tumor suppressor early growth response 1 in synovial sarcoma. Cancer Res 2008, 68:4303-4310.
• [37]Erkizan HV, Uversky VN, Toretsky JA: Oncogenic partnerships: EWS-FLI1 protein interactions initiate key pathways of Ewing's sarcoma. Clin Cancer Res 2010, 16:4077-4083.
• [38]Burdach S, Plehm S, Unland R, Dirksen U, Borkhardt A, Staege MS, Muller-Tidow C, Richter GH: Epigenetic maintenance of stemness and malignancy in peripheral neuroectodermal tumors by EZH2. Cell Cycle 2009, 8:1991-1996.
• [39]Riggi N, Suva ML, Suva D, Cironi L, Provero P, Tercier S, Joseph JM, Stehle JC, Baumer K, Kindler V, Stamenkovic I: EWS-FLI-1 expression triggers a Ewing's sarcoma initiation program in primary human mesenchymal stem cells. Cancer Res 2008, 68:2176-2185.
• [40]Candelaria M, Herrera A, Labardini J, González-Fierro A, Trejo-Becerril C, Taja-Chayeb L, Pérez-Cárdenas E, de la Cruz-Hernández E, Arias-Bofill D, Vidal S, Cervera E, Dueñas-Gonzalez A: Hydralazine and magnesium valproate as epigenetic treatment for myelodysplastic syndrome. Preliminary results of a phase-II trial. Ann Hematol 2010, 90:379-387.
• [41]Fu S, Hu W, Iyer R, Kavanagh JJ, Coleman RL, Levenback CF, Sood AK, Wolf JK, Gershenson DM, Markman M, Hennessy BT, Kurzrock R, Bast RC Jr: Phase 1b-2a study to reverse platinum resistance through use of a hypomethylating agent, azacitidine, in patients with platinum-resistant or platinum-refractory epithelial ovarian cancer. Cancer, in press.
• [42]Vigil CE, Martin-Santos T, Garcia-Manero G: Safety and efficacy of azacitidine in myelodysplastic syndromes. Drug Des Devel Ther 2010, 4:221-229.
• [43]Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A, Schoch R, Gattermann N, Sanz G, List A, Gore SD, Seymour JF, Bennett JM, Byrd J, Backstrom J, Zimmerman L, McKenzie D, Beach C, Silverman LR, International Vidaza High-Risk MDS Survival Study Group: Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol 2009, 10:223-232.
• [44]Kutko MC, Glick RD, Butler LM, Coffey DC, Rifkind RA, Marks PA, Richon VM, LaQuaglia MP: Histone deacetylase inhibitors induce growth suppression and cell death in human rhabdomyosarcoma in vitro. Clin Cancer Res 2003, 9:5749-5755.
• [45]Sakimura R, Tanaka K, Nakatani F, Matsunobu T, Li X, Hanada M, Okada T, Nakamura T, Matsumoto Y, Iwamoto Y: Antitumor effects of histone deacetylase inhibitor on Ewing's family tumors. Int J Cancer 2005, 116:784-792.
• [46]Hurtubise A, Bernstein ML, Momparler RL: Preclinical evaluation of the antineoplastic action of 5-aza-2'-deoxycytidine and different histone deacetylase inhibitors on human Ewing's sarcoma cells. Cancer Cell Int 2008, 8:16. BioMed Central Full Text
• [47]Fandy TE, Herman JG, Kerns P, Jiemjit A, Sugar EA, Choi SH, Yang AS, Aucott T, Dauses T, Odchimar-Reissig R, Licht J, McConnell MJ, Nasrallah C, Kim MK, Zhang W, Sun Y, Murgo A, Espinoza-Delgado I, Oteiza K, Owoeye I, Silverman LR, Gore SD, Carraway HE: Early epigenetic changes and DNA damage do not predict clinical response in an overlapping schedule of 5-azacytidine and entinostat in patients with myeloid malignancies. Blood 2009, 114:2764-2773.
• [48]Orzan F, Pellegatta S, Poliani L, Pisati F, Caldera V, Menghi F, Kapetis D, Marras C, Schiffer D, Finocchiaro G: Enhancer of Zeste 2 (Ezh2) is up-regulated in malignant gliomas and in glioma stem-like cells. Neuropathol Appl Neurobiol 2010, in press.
• [49]Yamaguchi J, Sasaki M, Sato Y, Itatsu K, Harada K, Zen Y, Ikeda H, Nimura Y, Nagino M, Nakanuma Y: Histone deacetylase inhibitor (SAHA) and repression of EZH2 synergistically inhibit proliferation of gallbladder carcinoma. Cancer Sci 2010, 101:355-362.
• [50]Fiskus W, Buckley K, Rao R, Mandawat A, Yang Y, Joshi R, Wang Y, Balusu R, Chen J, Koul S, Joshi A, Upadhyay S, Atadja P, Bhalla KN: Panobinostat treatment depletes EZH2 and DNMT1 levels and enhances decitabine mediated de-repression of JunB and loss of survival of human acute leukemia cells. Cancer Biol Ther 2009, 8:939-950.
• [51]Hayden A, Johnson PW, Packham G, Crabb SJ: S-adenosylhomocysteine hydrolase inhibition by 3-deazaneplanocin A analogues induces anti-cancer effects in breast cancer cell lines and synergy with both histone deacetylase and HER2 inhibition. Breast Cancer Res Treat, in press.
• [52]Kalushkova A, Fryknäs M, Lemaire M, Fristedt C, Agarwal P, Eriksson M, Deleu S, Atadja P, Osterborg A, Nilsson K, Vanderkerken K, Oberg F, Jernberg-Wiklund H: Polycomb target genes are silenced in multiple myeloma. PLoS One 2010, 5:e11483.
• [53]Fiskus W, Wang Y, Sreekumar A, Buckley KM, Shi H, Jillella A, Ustun C, Rao R, Fernandez P, Chen J, Balusu R, Koul S, Atadja P, Marquez VE, Bhalla KN: Combined epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin A and the histone deacetylase inhibitor panobinostat against human AML cells. Blood 2009, 114:2733-2743.
• [54]Tan J, Yang X, Zhuang L, Jiang X, Chen W, Lee PL, Karuturi RK, Tan PB, Liu ET, Yu Q: Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells. Genes Dev 2007, 21:1050-1063.
• [55]Wicha MS: Development of 'synthetic lethal' strategies to target BRCA1-deficient breast cancer. Breast Cancer Res 2009, 11:108. BioMed Central Full Text
• [56]Viré E, Brenner C, Deplus R, Blanchon L, Fraga M, Didelot C, Morey L, Van Eynde A, Bernard D, Vanderwinden JM, Bollen M, Esteller M, Di Croce L, de Launoit Y, Fuks F: The Polycomb group protein EZH2 directly controls DNA methylation. Nature 2006, 439:871-874.
• [57]Yu Y, Zeng P, Xiong J, Liu Z, Berger SL, Merlino G: Epigenetic drugs can stimulate metastasis through enhanced expression of the pro-metastatic Ezrin gene. PLoS One 2010, 5:e12710.
• [58]Herman JG, Gore S, Mufti G, Fenaux P, Santini V, Silverman L, Seymour J, Griffiths E, Caraway H, MacBeth K, Mckenzie D, Backstrom J, Beach CL: Abstract #4746: Relationship among gene methylation, azacitidine treatment, and survival in patients with higher-risk myelodysplastic syndromes (MDS): results from the AZA-001 trial. In AACR Meeting Abstracts. American Association for Cancer Reasearch, Philadelphia, PA; 2009.
• [59]Tuma RS: Epigenetic therapies move into new territory, but how exactly do they work? J Natl Cancer Inst 2009, 101:1300-1301.
• [60]Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, Heinrich MC, Tuveson DA, Singer S, Janicek M, Fletcher JA, Silverman SG, Silberman SL, Capdeville R, Kiese B, Peng B, Dimitrijevic S, Druker BJ, Corless C, Fletcher CD, Joensuu H: Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. New Eng J Med 2002, 347:472-480.
• [61]Blanke CD, Rankin C, Demetri GD, Ryan CW, von Mehren M, Benjamin RS, Raymond AK, Bramwell VH, Baker LH, Maki RG, et al.: Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol 2008, 26:626-632.
• [62]Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J, McArthur G, Judson IR, Heinrich MC, Morgan JA, Desai J, Fletcher CD, George S, Bello CL, Huang X, Baum CM, Casali PG: Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 2006, 368:1329-1338.
• [63]Mahmood ST, Agresta S, Vigil C, Zhao X, Han G, D'Amato G, Calitri CE, Dean M, Garrett C, Schell MJ, Antonia S, Chiappori A: Phase II study of sunitinib malate, a multi-targeted tyrosine kinase inhibitor in patients with relapsed or refractory soft tissue sarcomas. Focus on 3 prevalent histologies: Leiomyosarcoma, liposarcoma, and malignant fibrous histiocytoma. Int J Cancer, in press.
• [64]George S, Merriam P, Maki RG, Van den Abbeele AD, Yap JT, Akhurst T, Harmon DC, Bhuchar G, O'Mara MM, D'Adamo DR, Morgan J, Schwartz GK, Wagner AJ, Butrynski JE, Demetri GD, Keohan ML: Multicenter phase II trial of sunitinib in the treatment of nongastrointestinal stromal tumor sarcomas. J Clin Oncol 2009, 27:3154-3160.
• [65]Keohan ML, Morgan JA, D'Adamo DR, Harmon D, Butrynski JE, Wagner AJ, Schwartz GK, Maki RG, Demetri GD, George S: Continuous daily dosing (CDD) of sunitinib (SU) in patients with metastatic soft tissue sarcomas (STS) other than GIST: Results of a phase II trial. In ASCO Meeting Abstracts. Volume 26. American Society of Clinical Oncology, Alexandria, VA; 2008::10533.
• [66]Maki RG, Keohan ML, Undevia SD, Livingston M, Cooney MM, Elias A, Saulle MF, Wright JJ, D'Adamo DR, Schuetze SM, Sorafenib Sarcoma Study Group: Updated results of a phase II study of oral multi-kinase inhibitor sorafenib in sarcomas, CTEP study #7060. In ASCO Meeting Abstracts. Volume 26. American Society of Clinical Oncology, Alexandria, VA; 2008::10531.
• [67]Ryan CW, von Mehren M, Rankin CJ, Goldblum JR, Demetri GD, Bramwell VH, Borden EC: Phase II intergroup study of sorafenib (S) in advanced soft tissue sarcomas (STS): SWOG 0505. In ASCO Meeting Abstracts. Volume 26. American Society of Clinical Oncology, Alexandria, VA; 2008::10532.
• [68]Bertuzzi A, Stroppa EM, Secondino S, Pedrazzoli P, Zucali P, Quagliuolo V, Comandone A, Basso U, Soto Parra HJ, Santoro A: Efficacy and toxicity of sorafenib monotherapy in patients with advanced soft tissue sarcoma failing anthracycline-based chemotherapy. In ASCO Meeting Abstracts. Volume 28. American Society of Clinical Oncology, Alexandria, VA; 2010::10025.
• [69]Sleijfer S, Ray-Coquard I, Papai Z, Le Cesne A, Scurr M, Schöffski P, Collin F, Pandite L, Marreaud S, De Brauwer A, van Glabbeke M, Verweij J, Blay JY: Pazopanib, a multikinase angiogenesis inhibitor, in patients with relapsed or refractory advanced soft tissue sarcoma: a phase II study from the European organisation for research and treatment of cancer-soft tissue and bone sarcoma group (EORTC study 62043). J Clin Oncol 2009, 27:3126-3132.
• [70]Demetri GD, Casali PG, Blay JY, von Mehren M, Morgan JA, Bertulli R, Ray-Coquard I, Cassier P, Davey M, Borghaei H, Pink D, Debiec-Rychter M, Cheung W, Bailey SM, Veronese ML, Reichardt A, Fumagalli E, Reichardt P: A phase I study of single-agent nilotinib or in combination with imatinib in patients with imatinib-resistant gastrointestinal stromal tumors. Clin Cancer Res 2009, 15:5910-5916.
• [71]Okuno S, Bailey H, Mahoney MR, Adkins D, Maples W, Fitch T, Ettinger D, Erlichman C, Sarkaria JN: A phase 2 study of temsirolimus (CCI-779) in patients with soft tissue sarcomas: A study of the mayo phase 2 consortium (P2C). Cancer 2011, in press.
• [72]Richter S, Pink D, Hohenberger P, Schuette H, Casali PG, Pustowka A, Reichardt P: Multicenter, triple-arm, single-stage, phase II trial to determine the efficacy and safety of everolimus (RAD001) in patients with refractory bone or soft tissue sarcomas including GIST. In ASCO Meeting Abstracts. Volume 28. American Society of Clinical Oncology, Alexandria, VA; 2010::10038.
• [73]Mita MM, Britten CD, Poplin E, Tap WD, Carmona A, Yonemoto L, Wages DS, Bedrosian CL, Rubin EH, Tolcher AW: Deforolimus trial 106- A Phase I trial evaluating 7 regimens of oral Deforolimus (AP23573, MK-8669). ASCO Meeting Abstracts 2008, 26(Suppl):3509..
• [74]Chawla SP, Tolcher AW, Staddon AP, Schuetze S, D'Amato GZ, Blay JY, Loewy J, Kan R, Demetri GD: Survival results with AP23573, a novel mTOR inhibitor, in patients (pts) with advanced soft tissue or bone sarcomas: Update of phase II trial. ASCO Meeting Abstracts 2007, 2:5(Suppl):10076.
• [75]Anonymous: Ridaforolimus. Drugs R&D 2010, 10:165-178.
• [76]Olmos D, Postel-Vinay S, Molife LR, Okuno SH, Schuetze SM, Paccagnella ML, Batzel GN, Yin D, Pritchard-Jones K, Judson I, Worden FP, Gualberto A, Scurr M, de Bono JS, Haluska P: Safety, pharmacokinetics, and preliminary activity of the anti-IGF-1R antibody figitumumab (CP-751,871) in patients with sarcoma and Ewing's sarcoma: a phase 1 expansion cohort study. Lancet Oncol 2010, 11:129-135.
• [77]Patel S, Pappo A, Crowley J, Reinke D, Eid J, Ritland S, Chawla S, Staddon A, Maki R, Vassal G, Helman L, Sarcoma Alliance for Research and Collaboration: A SARC global collaborative phase II trial of R1507, a recombinant human monoclonal antibody to the insulin-like growth factor-1 receptor (IGF1R) in patients with recurrent or refractory sarcomas. ASCO Meeting Abstracts 2009, 27(Suppl):10503..
• [78]Tolcher AW, Sarantopoulos J, Patnaik A, Papadopoulos K, Lin CC, Rodon J, Murphy B, Roth B, McCaffery I, Gorski KS, Kaiser B, Zhu M, Deng H, Friberg G, Puzanov I: 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, 27:5800-5807.
• [79]Scartozzi M, Bianconi M, Maccaroni E, Giampieri R, Berardi R, Cascinu S: Dalotuzumab, a recombinant humanized mAb targeted against IGFR1 for the treatment of cancer. Curr Opin Mol Ther 2010, 12:361-371.