Dataset Information

The Controversial Role of Autophagy in Ewing Sarcoma Pathogenesis-Current Treatment Options.

ABSTRACT: Ewing Sarcoma (ES) is a rare, aggressive, and highly metastasizing cancer in children and young adults. Most ES cases carry the fusion of the Ewing Sarcoma Breakpoint Region 1 (EWSR1) and FLI1 (Friend leukemia virus integration site 1) genes, leading to an EWS-FLI1 fused protein, which is associated with autophagy, a homeostatic and catabolic mechanism under normal and pathological conditions. Following such interesting and controversial data regarding autophagy in ES, many clinical trials using modulators of autophagy are now underway in this field. In the present review, we summarize current data and clinical trials that associate autophagy with ES. In vitro studies highlight the controversial role of autophagy as a tumor promoter or a tumor suppressor mechanism in ES. Clinical and in vitro studies on ES, together with the autophagy modulators, suggest that caution should be adopted in the application of autophagy as a therapeutic target. Monitoring and targeting autophagy in every ES patient could eliminate the need for targeting multiple pathways in order to achieve the maximum beneficial effect. Future studies are required to focus on which ES patients are affected by autophagy modulators in order to provide novel and more efficient therapeutic protocols for patients with ES based on the current autophagy status of the tumors.

SUBMITTER: Koustas E

PROVIDER: S-EPMC7996923 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description: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.

Project description:Ewing sarcoma is the second most common bone sarcoma in children after osteosarcoma. It is a very aggressive malignancy for which systemic treatment has greatly improved outcome for patients with localized disease, who now see survival rates of over 70%. However, for the quarter of patients presenting with metastatic disease, survival is still dismal with less than 30% of patients surviving past 5 years. Patients with disease relapse, local or distant, face an even poorer prognosis with an event-free 5-year survival rate of only 10%. Unfortunately, Ewing sarcoma patients have not yet seen the benefit of recent years' technical achievements such as next-generation sequencing, which have enabled researchers to study biological systems at a level never seen before. In spite of large multinational studies, treatment of Ewing sarcoma relies entirely on chemotherapeutic agents that have been largely unchanged for decades. As many promising modern therapies, including monoclonal antibodies, small molecules, and immunotherapy, have been disappointing to date, there is no clear candidate as to which drug should be investigated in the next large-scale clinical trial. However, the mechanisms driving tumor development in Ewing sarcoma are slowly unfolding. New entities of Ewing-like tumors, with fusion transcripts that are related to the oncogenic EWSR1-FLI1 fusion seen in the majority of Ewing tumors, are being mapped. These tumors, although sharing much of the same morphologic features as classic Ewing sarcoma, behave differently and may require a different treatment. There are also controversies regarding local treatment of Ewing sarcoma. The radiosensitive nature of the disease and the tendency for Ewing sarcoma to arise in the axial skeleton make local treatment very challenging. Surgical treatment and radiotherapy have their pros and cons, which may give rise to different treatment strategies in different centers around the world. This review article discusses some of these controversies and reproduces the highlights from recent publications with regard to diagnostics, systemic treatment, and surgical treatment of Ewing sarcoma.

Dataset Information

The Controversial Role of Autophagy in Ewing Sarcoma Pathogenesis-Current Treatment Options.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets