4.6 Review

Ewing sarcoma treatment: a gene therapy approach

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Novel Targeted Therapeutic Strategies for Ewing Sarcoma

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Summary: Ewing sarcoma is a rare malignant bone tumor with a high recurrence rate. This study identifies new therapeutic targets, particularly the EWSR1/FLI1 fusion protein, and proposes experimental therapy targeting multiple signaling pathways for improved patient survival.

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Ewing's Sarcoma

Nicolo Riggi et al.

Summary: Ewing's sarcoma is an aggressive cancer that primarily affects children and young adults. In 85 to 90% of cases, a t(11;22) translocation is present. Treatment typically involves surgery, radiotherapy, and chemotherapy, with a 5-year survival rate of around 70%.

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The translational repressor 4E-BP1 regulates RRM2 levels and functions as a tumor suppressor in Ewing sarcoma tumors

Kelli L. Goss et al.

Summary: Ribonucleotide reductase (RNR) is a key enzyme in DNA replication and repair that is regulated by fluctuations in the level of the RRM2 subunit. 4E-BP1, a repressor of cap-dependent protein translation, specifically controls the level of the RRM2 protein. Inhibition of mTORC1/2 reduces protein synthesis and decreases the level of the RRM2 protein, suggesting a regulatory link between protein translation and DNA replication.

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Class I histone deacetylases (HDAC) critically contribute to Ewing sarcoma pathogenesis

Oxana Schmidt et al.

Summary: Histone deacetylases (HDACs) class I are continuously expressed in Ewing sarcoma (EwS), with patients having high levels of individual class I HDAC expression showing decreased overall survival. Knockout of HDAC1 and HDAC2 inhibited invasiveness in EwS cells and blocked tumor growth in xenograft mice. Treatment with HDAC inhibitors enhanced susceptibility to chemotherapeutics and mimicked the effects of EZH2 RNAi, suggesting potential for combination therapy in treating this malignant disease.

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Sarcoma IL-12 overexpression facilitates NK cell immunomodulation

Mary Jo Rademacher et al.

Summary: Lentiviral transduction of sarcoma cells to express IL-12 can induce high-level expression of IL-12 and elicit specific immune responses in murine models, particularly mature human NK cells. IL-12 immunomodulation through autologous tumor transduction and reintroduction shows promise for sarcoma treatment and warrants further exploration.

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TRIM8 modulates the EWS/FLI oncoprotein to promote survival in Ewing sarcoma

Bo Kyung A. Seong et al.

Summary: Fusion-transcription factors (fusion-TFs) are difficult to therapeutically target, but recent research has discovered TRIM8 as a selective E3 ubiquitin ligase for degrading a driver fusion-TF in Ewing sarcoma. Knocking out TRIM8 leads to increased levels of the fusion TF, EWS/FLI, providing a potential strategy for exploiting oncogene overdose in Ewing sarcoma and other fusion-TF driven cancers.

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Therapeutic Potential of EWSR1-FLI1 Inactivation by CRISPR/Cas9 in Ewing Sarcoma

Saint T. Cervera et al.

Summary: Ewing sarcoma is an aggressive bone cancer affecting children and young adults, characterized by chromosomal translocations producing chimeric oncogenic transcription factors. In this study, genetic inactivation of the EWSR1-FLI1 oncogene using CRISPR/Cas9 technology in Ewing sarcoma cells effectively blocked cell proliferation and induced a senescence phenotype. This suggests that complete inactivation of EWSR1-FLI1 at the cellular level could be a promising therapeutic approach in the future.

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Viral vector platforms within the gene therapy landscape

Jote T. Bulcha et al.

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EWS/ETS-Driven Ewing Sarcoma Requires BET Bromodomain Proteins

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Genome-scale CRI SPR-Cas9 screen identifies druggable dependencies in TP53 wild-type Ewing sarcoma

Bjorn Stolte et al.

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Efficient Recreation of t(11;22) EWSR1-FLI1+ in Human Stem Cells Using CRISPR/Cas9

Raul Torres-Ruiz et al.

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Cadherin-11 regulates the metastasis of Ewing sarcoma cells to bone

Mihoko Hatano et al.

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Cancer translocations in human cells induced by zinc finger and TALE nucleases

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Modeling Initiation of Ewing Sarcoma in Human Neural Crest Cells

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Advances in Ewing's Sarcoma Research: Where Are We Now and What Lies Ahead?

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A Molecular Function Map of Ewing's Sarcoma

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GLI1 Is a Central Mediator of EWS/FLI1 Signaling in Ewing Tumors

Jay Joo et al.

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Targeting Lyn inhibits tumor growth and metastasis in Ewing's sarcoma

Hui Guan et al.

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A preclinical model for predicting drug response in soft-tissue sarcoma with targeted AAVP molecular imaging

Amin Hajitou et al.

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