Enhancer of zeste homolog 2 (EZH2) in pediatric soft tissue sarcomas: first implications
© Ciarapica et al; licensee BioMed Central Ltd. 2011
Received: 2 February 2011
Accepted: 25 May 2011
Published: 25 May 2011
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.
KeywordsEZH2 soft tissue sarcomas epigenetics methylation methyltransferases
Soft tissue sarcomas: a clinical challenge
Targeted therapy clinical studies for soft tissue sarcoma (STS)
Biological molecular agents
Clinical studies (phase) and clinical efficiency
Tyrosine kinase inhibitors (TKIs)
Imatinib mesylate (IM)
Phase II study: 53.7% of patients with GISTs showed a partial response, 27.9% of patients showed stable disease, 13.6% of patients showed early resistance to imatinib, 5% of patients showed serious adverse events
Phase III study: confirmation of the effectiveness of imatinib as primary systemic therapy for patients with incurable GIST. No advantages to higher dose treatment were reported.
Sunitinib malate (SM)
VEGF-R1, VEGF-R2, VEGF-R3, c-Kit, PDGFR, Flt-3, CSF1, neurotrophic factor receptors
Phase III study: 7% of patients with GIST showed partial response, 58% had stable disease, 19% had progressive disease; 27.3 weeks was the time-to-tumor progression for sunitinib vs 6.4 weeks for placebo. Progression-free survival was similar.
Phase II study: 3-month progression-free rate of >40% for liposarcomas leiomyosarcomas
Phase II study: 52% of patients showed metabolic stable disease, 20% of patients achieved stable disease for at least 16 weeks, 47% of patients achieved partial response
Phase II study (current): SM activity in patients with certain subtypes of STS. The majority of these patients showed stable disease for 16 weeks.
VEGF-R2, VEGF-R3, c-Kit, PDGFR, Raf/Mek/Erk
Phase II study: 14% of patients with angiosarcoma and 6% of patients with leiomyosarcoma had a response, 64% of patients developed intolerance at the drug dose used
Phase II study: 78% patients with vascular tumors showed disease stabilization
Phase II study (current): antitumor activity and acceptable toxicity profile in patients with antracycline-refractory STS
Phase II study: 12-week progression-free survival was reached by 44% patients with leiomyosarcoma, 49% of patients with synovial sarcomas, and 39% of patients with the other STS types
BCR/ABL, c-Kit, PDGFR, CSF1R
Phase I study: nilotinib alone or in combination with imatinib was well tolerated and showed clinical activity in imatinib-resistant GIST patients
Mammalian target of rapamycin (mTOR) inhibitors
Phase II study: moderate toxicity and limited clinical activity
Phase II study: acceptable toxicity. Limited clinical activity in heavily pretreated patients with bone and soft tissue sarcomas. The efficacy in imatinib-refractory and sunitinib-refractory GIST is promising.
Phase I study: safety of the drug; 27% of patients showed stable disease.
Phase II study: 29% of clinical benefit rate. Prolongation of survival.
Phase III study (current)
Insulin-like growth factor (IGF) receptor antibodies
Phase I study: good tolerance of the drug
Phase II study (current): R1507 is well tolerated. Significant activity has been observed in Ewing's sarcoma, RMS and OS with several dramatic responses seen in Ewing's sarcoma and RMS.
Phase I study: absence of severe toxicities
Phase I study (current)
The Polycomb group protein EZH2 in STS
EZH2 in RMS
EZH2 in synovial sarcoma
Synovial sarcoma is a malignant cancer that affects prevalently young patients and represents almost 10% of all STSs . It is characterized by the typical translocation t(X;18)(p11;q11) that generates the fusion between the synovial sarcoma translocation, chromosome 18 (SS18 or SYT) gene on chromosome 18 and either synovial sarcoma, X breakpoint 1, 2 or 4 (SSX1, SSX2 or SSX4) genes on the X chromosome . Previously reported data showed that chimerical proteins SYT-SSX might disrupt gene expression mechanisms by functionally interacting with PcG proteins in synovial cells . In particular, SYT-SSX2 fusion protein induces downstream target-gene deregulation through epigenetic mechanisms . Recently, EZH2 has been found to mediate the effects of SYT-SSX activity. Specifically, SYT-SSX2 represses the expression of the tumor suppressor gene early growth response 1 (EGR1), a regulator of cell cycle, engaging EZH2 on the EGR1 promoter in synovial sarcoma cells (Figure 2b). EGR1 repression has been found to be associated with H3K27 trimethylation, and EZH2 and the PRC1 component BMI1 have been shown to directly bind its promoter, thus supporting the existence of a novel epigenetic mechanism of oncogenesis in synovial sarcoma . This finding illustrates how a genetic lesion that generates an oncogenic trascriptional regulator might exploit EZH2 and other epigenetic regulators to sustain tumorigenesis.
EZH2 in Ewing's sarcoma
Ewing's sarcoma is an embryonal malignancy characterized by the t(11;22)(q24;q12) translocation which generates chimerical Ewing sarcoma (EWS)/ETS fusion transcription factors. One of the most common fusion protein found in patients affected by this tumor is EWS/Friend leukemia integration 1 transcription factor (FLI1) . EZH2 is expressed at high levels in Ewing's tumors . Studying the influence of EZH2 downregulation on gene expression, Richter and colleagues found that EZH2 is responsible for the undifferentiated phenotype of Ewing's sarcoma by maintaining a stemness gene expression signature, inhibiting differentiation . Strikingly, EWS/FLI1 has been found to induce the expression of EZH2 by direct binding to its promoter in both Ewing's sarcoma cell lines and human MSCs (Figure 2c) . EWS/FLI1-dependent activation of EZH2 seems to be specific, because the other components of the PRC2/3 complex are not affected . Notably, human MSCs seem to represent a permissive environment for the expression of EWS/FLI1, which induces features in these cells that recapitulate Ewing's sarcoma biology. This observation may implicate EZH2 as a coinitiator of Ewing's sarcoma . Data from these studies offer an example of how a translocation-derived fusion product takes advantage of EZH2 recruiting this methyltransferase to drive tumor progression at the expenses of differentiation.
Concluding remarks and future perspectives
Pediatric STSs, especially those metastatic at diagnosis, are highly aggressive tumors for which there is still an unmet medical need of more effective and less toxic therapeutic approaches. The role of the epigenetic regulator EZH2 in maintaining the embryonal cell phenotype of STS, its overexpression in these cancers and its functional interaction with many fusion proteins typical of STS, suggest that EZH2 may represent both a potential marker of undifferentiated precancerous cells and a reasonable candidate therapeutic target in STS. Increasing attention is focusing on epigenetic therapies that have provided promising results in clinical trials for some human tumors [40–42]. The clinical effectiveness of epigenetic therapies in human malignancies has been recently proved by the observation that, in a randomized phase III trial, the DNA hypomethylating agent azacytidine prolonged overall survival of myelodysplastic syndrome (MDS) patients compared to other standard therapies . The potential efficacy of epigenetic therapy in STS is supported by preclinical studies employing HDAC inhibitors [36, 44–46]. Many studies on cell culture and animal models indicate that diverse epigenetic processes synergize to control gene expression. Hence, different kinds of epigenetic drugs, such as DNA-demethylating agents and HDAC inhibitors, have been included in combination treatment protocols [40, 47]. It is noteworthy that, in Ewing's sarcoma cells, HDAC inhibitor treatment in vitro induces downregulation of EZH2 , as more recently confirmed in glioma , gallbladder carcinoma  and acute myeloid leukemia . Consistently, in preclinical models of different cancers, the antitumor effect of EZH2 inhibition, obtained through the methyltransferase inhibitor 3'-deazanoplanocin (DZNep), is enhanced by addition of HDAC inhibitors [51–53]. DZNep has been shown to act by causing depletion of PRC2 subunits with subsequent reactivation of PRC2-silenced genes [54, 55]. In addition, it has been shown that the repressive function of EZH2 on gene expression is strengthened by the role of DNMTs, with which EZH2 physically interacts regulating their activity . In this view, additional usage of DNMTs inhibitors in protocols targeting EZH2 might improve response in some tumor contexts. In turn, since HMTs are also active in non-proliferating cells, the inclusion of EZH2 inhibitors in combination regimens may overcome the ineffectiveness of DNMTs inhibitors in quiescent cells. On the other hand, it must be noted that, due to the complexity of molecular crosstalk involved in epigenetic control, the use of epigenetic drugs affecting a variety of molecular networks entails the risk of unforeseeable effects. For instance, despite their antiproliferative effects in vitro, treatments employing either HDACs or DNA methylation inhibitors have been recently reported to increase in vivo the invasive capabilities of RMS cells through upregulation of the prometastatic gene Ezrin . Major questions remain open on the in vivo mechanism(s) of action of epigenetic drugs. Indeed, the clinical response to azacytidine in terms of prolongation of survival in MDS patients does not appear to be directly correlated with methylation of specific tumor suppressor genes, though methylation status has been shown to correlate with poor survival . Even if future preclinical studies will better clarify the mechanisms of action of these drugs on gene expression, preclinical findings will need to be validated in humans .
Despite these unresolved questions, epigenetic therapy is a promising approach for targeted anticancer therapies in pediatric STS. Available evidence suggests that targeting the methyltransferase EZH2 may be potentially able to restore physiological patterns of gene expression in pediatric STS. In the future, modulation of EZH2 activity may provide a new line of intervention that could be combined with epigenetic drugs acting on other molecular targets and/or conventional cytotoxic agents to treat these aggressive pediatric tumors.
The present work was supported by grants from Ministero della Sanità Italia (Ricerca Corrente), Associazione Italiana per la Ricerca sul Cancro (AIRC Project 10338) and Istituto Superiore di Sanità (ISS Project 70BF/8) to RR and by grants from Ministero della Salute, Italia (Ricerca Corrente) and AIRC (Special Project 5 × mille) to FL.
- 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. 10.2174/157488810790442859.View ArticlePubMedPubMed CentralGoogle Scholar
- Jemal A, Siegel R, Xu J, Ward E: Cancer statistics, 2010. CA Cancer J Clin. 2010, 60: 277-300. 10.3322/caac.20073.View ArticlePubMedGoogle Scholar
- Vincenzi B, Frezza AM, Santini D, Tonini G: New therapies in soft tissue sarcoma. Expert Opin Emerg Drugs. 2010, 15: 237-248. 10.1517/14728211003592108.View ArticlePubMedGoogle Scholar
- Ganjoo KN: New developments in targeted therapy for soft tissue sarcoma. Curr Oncol Rep. 2010, 12: 261-265. 10.1007/s11912-010-0107-2.View ArticlePubMedGoogle Scholar
- Krikelis D, Judson I: Role of chemotherapy in the management of soft tissue sarcomas. Expert Rev Anticancer Ther. 2010, 10: 249-260. 10.1586/era.09.176.View ArticlePubMedGoogle Scholar
- Yoo CB, Jones PA: Epigenetic therapy of cancer: past, present and future. Nat Rev Drug Discov. 2006, 5: 37-50. 10.1038/nrd1930.View ArticlePubMedGoogle Scholar
- Simon JA, Lange CA: Roles of the EZH2 histone methyltransferase in cancer epigenetics. Mutat Res. 2008, 647: 21-29.View ArticlePubMedGoogle Scholar
- Sparmann A, van Lohuizen M: Polycomb silencers control cell fate, development and cancer. Nat Rev Cancer. 2006, 6: 846-856. 10.1038/nrc1991.View ArticlePubMedGoogle Scholar
- Ringrose L, Paro R: Epigenetic regulation of cellular memory by the Polycomb and Trithorax group proteins. Annu Rev Genet. 2004, 38: 413-443. 10.1146/annurev.genet.38.072902.091907.View ArticlePubMedGoogle Scholar
- 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. 10.1634/stemcells.2006-0608.View ArticlePubMedGoogle Scholar
- Schuettengruber B, Chourrout D, Vervoort M, Leblanc B, Cavalli G: Genome regulation by polycomb and trithorax proteins. Cell. 2007, 128: 735-745. 10.1016/j.cell.2007.02.009.View ArticlePubMedGoogle Scholar
- 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. 10.1093/emboj/16.11.3219.View ArticlePubMedPubMed CentralGoogle Scholar
- 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. 10.1073/pnas.1933744100.View ArticlePubMedPubMed CentralGoogle Scholar
- 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. 10.1038/nature01075.View ArticlePubMedGoogle Scholar
- 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. 10.1073/pnas.0409875102.View ArticlePubMedPubMed CentralGoogle Scholar
- 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. 10.4161/cc.8.1.7292.View ArticlePubMedGoogle Scholar
- 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. 10.1073/pnas.0810759106.View ArticlePubMedPubMed CentralGoogle Scholar
- De Giovanni C, Landuzzi L, Nicoletti G, Lollini PL, Nanni P: Molecular and cellular biology of rhabdomyosarcoma. Future Oncol. 2009, 5: 1449-1475. 10.2217/fon.09.97.View ArticlePubMedGoogle Scholar
- 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. 10.1016/j.canlet.2008.09.039.View ArticlePubMedGoogle Scholar
- Merlino G, Helman LJ: Rhabdomyosarcoma--working out the pathways. Oncogene. 1999, 18: 5340-5348. 10.1038/sj.onc.1203038.View ArticlePubMedGoogle Scholar
- 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. 10.1200/JCO.2009.26.3814.View ArticlePubMedGoogle Scholar
- 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. 10.1200/JCO.2008.21.1268.View ArticlePubMedPubMed CentralGoogle Scholar
- 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. 10.1158/0008-5472.CAN-05-4578.View ArticlePubMedGoogle Scholar
- 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. 10.1002/path.2170.View ArticlePubMedGoogle Scholar
- 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. 10.1016/j.ccr.2008.10.006.View ArticlePubMedGoogle Scholar
- 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. AACR Meeting Abstracts. 2010, American Association for Cancer Reasearch, Philadelphia, PAGoogle Scholar
- 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. 10.1101/gad.1241904.View ArticlePubMedPubMed CentralGoogle Scholar
- 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. 10.1016/j.molcel.2009.08.008.View ArticlePubMedPubMed CentralGoogle Scholar
- Wong CF, Tellam RL: MicroRNA-26a targets the histone methyltransferase Enhancer of Zeste homolog 2 during myogenesis. J Biol Chem. 2008, 283: 9836-9843. 10.1074/jbc.M709614200.View ArticlePubMedGoogle Scholar
- 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. 10.1128/MCB.02020-06.View ArticlePubMedPubMed CentralGoogle Scholar
- 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. 10.1038/sj.onc.1210836.View ArticlePubMedGoogle Scholar
- 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. 10.1002/mpo.1175.View ArticlePubMedGoogle Scholar
- 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.PubMedPubMed CentralGoogle Scholar
- 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. 10.1038/sj.onc.1202613.View ArticlePubMedGoogle Scholar
- 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. 10.1158/0008-5472.CAN-05-3726.View ArticlePubMedGoogle Scholar
- 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. 10.1158/0008-5472.CAN-08-0092.View ArticlePubMedGoogle Scholar
- 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. 10.1158/1078-0432.CCR-09-2261.View ArticlePubMedPubMed CentralGoogle Scholar
- 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. 10.4161/cc.8.13.8929.View ArticlePubMedGoogle Scholar
- 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. 10.1158/0008-5472.CAN-07-1761.View ArticlePubMedGoogle Scholar
- 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.View ArticlePubMedGoogle Scholar
- 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: 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.
- Vigil CE, Martin-Santos T, Garcia-Manero G: Safety and efficacy of azacitidine in myelodysplastic syndromes. Drug Des Devel Ther. 2010, 4: 221-229.View ArticlePubMedPubMed CentralGoogle Scholar
- 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. 10.1016/S1470-2045(09)70003-8.View ArticlePubMedPubMed CentralGoogle Scholar
- 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.PubMedGoogle Scholar
- 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. 10.1002/ijc.21069.View ArticlePubMedGoogle Scholar
- 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: 16-10.1186/1475-2867-8-16.View ArticlePubMedPubMed CentralGoogle Scholar
- 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.View ArticlePubMedPubMed CentralGoogle Scholar
- 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.Google Scholar
- 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. 10.1111/j.1349-7006.2009.01387.x.View ArticlePubMedGoogle Scholar
- 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. 10.4161/cbt.8.10.8213.View ArticlePubMedPubMed CentralGoogle Scholar
- 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.
- 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: e11483-10.1371/journal.pone.0011483.View ArticlePubMedPubMed CentralGoogle Scholar
- 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.View ArticlePubMedPubMed CentralGoogle Scholar
- 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. 10.1101/gad.1524107.View ArticlePubMedPubMed CentralGoogle Scholar
- Wicha MS: Development of 'synthetic lethal' strategies to target BRCA1-deficient breast cancer. Breast Cancer Res. 2009, 11: 108-10.1186/bcr2362.View ArticlePubMedPubMed CentralGoogle Scholar
- 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. 10.1038/nature04431.View ArticlePubMedGoogle Scholar
- 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: e12710-10.1371/journal.pone.0012710.View ArticlePubMedPubMed CentralGoogle Scholar
- 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. AACR Meeting Abstracts. 2009, American Association for Cancer Reasearch, Philadelphia, PAGoogle Scholar
- Tuma RS: Epigenetic therapies move into new territory, but how exactly do they work?. J Natl Cancer Inst. 2009, 101: 1300-1301. 10.1093/jnci/djp342.View ArticlePubMedGoogle Scholar
- 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. 10.1056/NEJMoa020461.View ArticlePubMedGoogle Scholar
- 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. 10.1200/JCO.2007.13.4452.View ArticlePubMedGoogle Scholar
- 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. 10.1016/S0140-6736(06)69446-4.View ArticlePubMedGoogle Scholar
- 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.
- 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. 10.1200/JCO.2008.20.9890.View ArticlePubMedPubMed CentralGoogle Scholar
- 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. ASCO Meeting Abstracts. 2008, American Society of Clinical Oncology, Alexandria, VA, 26 (Suppl): 10533.
- 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. ASCO Meeting Abstracts. 2008, American Society of Clinical Oncology, Alexandria, VA, 26 (Suppl): 10531.
- 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. ASCO Meeting Abstracts. 2008, American Society of Clinical Oncology, Alexandria, VA, 26 (Suppl): 10532.
- 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. ASCO Meeting Abstracts. 2010, American Society of Clinical Oncology, Alexandria, VA, 28 (Suppl): 10025.
- 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. 10.1200/JCO.2008.21.3223.View ArticlePubMedGoogle Scholar
- 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. 10.1158/1078-0432.CCR-09-0542.View ArticlePubMedPubMed CentralGoogle Scholar
- 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.Google Scholar
- 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. ASCO Meeting Abstracts. 2010, American Society of Clinical Oncology, Alexandria, VA, 28 (Suppl): 10038.
- 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..Google Scholar
- 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.Google Scholar
- Anonymous: Ridaforolimus. Drugs R&D. 2010, 10: 165-178.View ArticleGoogle Scholar
- 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. 10.1016/S1470-2045(09)70354-7.View ArticlePubMedGoogle Scholar
- 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..Google Scholar
- 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. 10.1200/JCO.2009.23.6745.View ArticlePubMedGoogle Scholar
- 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.PubMedGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1741-7015/9/63/prepub
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