molecular pathogenesis and targeted therapeutics in ewing sarcomaprimitive neuroectodermal tumours分子发病机制和有针对性的疗法在尤因sarcomaprimitive neuroectodermal肿瘤.pdfVIP

Kelleher and Thomas Clinical Sarcoma Research 2012, 2:6 /content/2/1/6 CLINICAL SARCOMA RESEARCH REVIEW Open Access Molecular pathogenesis and targeted therapeutics in Ewing sarcoma/primitive neuroectodermal tumours Fergal C Kelleher1,2* and David M Thomas2 Abstract Background: Ewing sarcoma/PNET is managed with treatment paradigms involving combinations of chemotherapy, surgery, and sometimes radiation. Although the 5-year survival rate of non-metastatic disease approaches 70%, those cases that are metastatic and those that recur have 5-year survival rates of less than 20%. Molecularly targeted treatments offer the potential to further improve treatment outcomes. Methods: A PUBMED search was performed from 1997 to 2011. Published literature that included the topic of the Ewing sarcoma/PNET was also referenced. Results: Insulin-like growth factor-1 receptor (IGF-1R) antagonists have demonstrated modest single agent efficacy in phase I/II clinical trials in Ewing sarcoma/PNET, but have a strong preclinical rationale. Based on in vitro and animal data, treatment using antisense RNA and cDNA oligonucleotides directed at silencing the EWS-FLI chimera that occurs in most Ewing sarcoma/PNET may have potential therapeutic importance. However drug delivery and degradation problems may limit this therapeutic approach. Protein-protein interactions can be targeted by inhibition of RNA helicase A, which binds to EWS/FLI as part of the transcriptional complex. Tumour necrosis factor related apoptosis inducing ligand induction using interferon has been used in preclinical models. Interferons may be incorporated into future chemotherapeutic treatment paradigms. Histone deacetylase inhibitors can restore TGF-b receptor II allowing TFF-b signalling, which appears to inh