Molecular pathogenesis and targeted therapeutics in Ewing sarcoma/primitive neuroectodermal tumours

Abstract

BackgroundEwing 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.MethodsA PUBMED search was performed from 1997 to 2011. Published literature that included the topic of the Ewing sarcoma/PNET was also referenced.ResultsInsulin-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-β receptor II allowing TFF-β signalling, which appears to inhibit growth of Ewing sarcoma/PNET cell lines in vitro. Immunotherapy using allogeneic natural killer cells has activity in Ewing sarcoma/PNET cell lines and xenograft models. Finally, cyclin dependent kinase inhibitors such as flavopiridol may be clinically efficacious in relapsed Ewing sarcoma/PNET.ConclusionPreclinical evidence exists that targeted therapeutics may be efficacious in the ESFT. IGF-1R antagonists have demonstrated efficacy in phase I/II clinical trials, although predicting responses remains a challenge. The future treatment of Ewing sarcoma/PNET is likely to be improved by these scientific advances.

A Novel Role for Keratin 17 in Coordinating Oncogenic Transformation and Cellular Adhesion in Ewing Sarcoma

“…In support of this are the findings that insulin-like growth factor 1 receptor (IGF1R) antagonists that have shown efficacy in phase I/II clinical trials for the treatment of Ewing sarcoma patients (65,66) inhibit not only PI3K-AKT signaling but also the RAS-mitogen-activated protein kinase (MAPK) and JAK-STAT pathways. Therefore, inhibition of multiple crucial signaling pathways may be necessary to inhibit growth and transformation of Ewing sarcoma cells.…”

Dural metastasis of Ewing′s sarcoma

“…Nowadays, molecular and biologically directed therapies are the attractive and emerging treatment modalities of Ewing’s sarcoma as targeting the autocrine signaling pathways, including the insulin-like growth factor has been shown to decrease proliferation and increase apoptosis. [183136] But its use according to van de Luijtgaarden et al , [42] could be more effective in first line than in refractory or recurrent diseases, like ours, which are the ones in need of new therapeutic options.…”

Therapeutic approach in glioblastoma multiforme with primitive neuroectodermal tumor components: Case report and review of the literature

“…Many advances in the understanding of cancer biology are made in the field of gene sequencing and interaction with tumor microenvironment. They aim to identify alterations of the immune system defing immune phenotypes (25,26) and cancer pathways associated with intracellular and intercellular signaling important to mediate cancer pathogenesis and progression (27)(28)(29)(30)(31)(32)(33).…”