Survivin, a target to modulate the radiosensitivity of Ewing’s sarcoma

Greve, Burkhard; Sheikh-Mounessi, F.; Kemper, Björn; Ernst, Iris; Götte, Martin; Eich, Hans Theodor

doi:10.1007/s00066-012-0223-z

Cited by 41 publications

(22 citation statements)

References 39 publications

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“…As shown in Fig. 1A, the top 20 genes ranked by median inhibition rate values (MV) included a number of known oncogenic kinases in Ewing sarcoma, such as ROR1, KIT, FGFR, PTK families (PTK-2 and 7), Src families (FGR and SRMS), ERBB4, and EGFR (9,(30)(31)(32)(33)(34)(35)(36)(37), which strongly supported the methodology and effectiveness of our high-throughput screen. Importantly, we identified novel targets including SYK and related proteins (SYK and ZAP70), BTK, ABL1, FLT4, and MATK.…”

Section: High-throughput Sirna and Small-molecule Inhibitor Library Ssupporting

confidence: 69%

Identification of a Novel SYK/c-MYC/MALAT1 Signaling Pathway and Its Potential Therapeutic Value in Ewing Sarcoma

Sun

Lin

Cao

et al. 2017

Clinical Cancer Research

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Ewing sarcoma (EWS) is a devastating soft tissue sarcoma affecting predominantly young individuals. Tyrosine kinases (TK) and associated pathways are continuously activated in many malignancies, including EWS; these enzymes provide candidate therapeutic targets. Two high-throughput screens (a siRNA library and a small-molecule inhibitor library) were performed in EWS cells to establish candidate targets. Spleen tyrosine kinase (SYK) phosphorylation was assessed in EWS patients and cell lines. SYK was inhibited by a variety of genetic and pharmacological approaches, and SYK-regulated pathways were investigated by cDNA microarrays. The transcriptional regulation of MALAT1 was examined by ChIP-qPCR, luciferase reporter, and qRT-PCR assays. SYK was identified as a candidate actionable target through both high-throughput screens. SYK was highly phosphorylated in the majority of EWS cells, and SYK inhibition by a variety of genetic and pharmacologic approaches markedly inhibited EWS cells both and Ectopic expression of SYK rescued the cytotoxicity triggered by SYK-depletion associated with the reactivation of both AKT and c-MYC. A long noncoding RNA, MALAT1, was identified to be dependent on SYK-mediated signaling. Moreover, c-MYC, a SYK-promoted gene, bound to the promoter of MALAT1 and transcriptionally activated MALAT1, which further promoted the proliferation of EWS cells. This study identifies a novel signaling involving SYK/c-MYC/MALAT1 as a promising therapeutic target for the treatment of EWS. .

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Section: High-throughput Sirna and Small-molecule Inhibitor Library Ssupporting

confidence: 69%

Identification of a Novel SYK/c-MYC/MALAT1 Signaling Pathway and Its Potential Therapeutic Value in Ewing Sarcoma

Sun

Lin

Cao

et al. 2017

Clinical Cancer Research

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“…Although molecular mechanistic studies have shed lights for exploring radiosensitive gene signatures [28, 29], till now, knowledge is still limited about the molecular determinants of tumor radiatiosensitivity in the clinical setting. The inability to understand the fundamental molecular basis for sarcoma sensitivity or resistance to radiation prevents a risk-based clinical trial as well as target driven therapeutic strategies.…”

Section: Discussionmentioning

confidence: 99%

Development of a radiosensitivity gene signature for patients with soft tissue sarcoma

Tang

Zeng

et al. 2017

Oncotarget

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Adjuvant radiotherapy is an important clinical treatment option for the majority of sarcomas. The motivation of current study is to identify a gene signature and to predict radiosensitive patients who are most likely to benefit from radiotherapy. Using the public available data of soft tissue sarcoma from The Cancer Genome Atlas, we developed a cross-validation procedure for identifying a gene signature and predicting radiosensitive patients through. The result showed that the predicted radiosensitive patients who received radiotherapy had a significantly better survival with a reduced rate of new tumor event and disease progression. Strata analysis showed that the predicted radiosensitive patients had significantly better survival under radiotherapy independent of histologic types. A hierarchical cluster analysis was used to validate the gene signature, and the results showed the predicted sensitivity for each patient well matched the results from cluster analysis. Together, we demonstrate a radiosensitive molecular signature that can be potentially used for identifying radiosensitive patients with sarcoma.

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“…The IAP family regulates cell death by inhibiting caspases or the assembly of pro-apoptotic protein complexes, and mediating the expression of anti-apoptotic proteins [57,58]. Since BIRC5 expression is associated with chemo- and radioresistance in Ewing sarcoma and poor patient prognosis [9,10], BIRC5 downregulation by Viscum album L. extracts makes it an interesting candidate for targeting Ewing sarcoma. We previously achieved a similar effect with acute myeloid leukemia cells [31].…”

Section: Discussionmentioning

confidence: 99%

“…Stage, anatomical localization, and tumor size influence prognosis [7]. Expression of the inhibitor of apoptosis protein (IAP) family member, BIRC5 (formerly survivin), is also a poor prognostic factor for Ewing sarcoma [9,10]. BIRC5 has been suggested as an attractive target for new anticancer agents, since it is expressed in many cancers but not in differentiated normal tissues [11].…”

Section: Introductionmentioning

confidence: 99%

Multiple Active Compounds from Viscum album L. Synergistically Converge to Promote Apoptosis in Ewing Sarcoma

Twardziok

Kleinsimon

Rolff³

et al. 2016

PLoS ONE

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Ewing sarcoma is the second most common bone cancer in children and adolescents, with poor prognosis and outcome in ~70% of initial diagnoses and 10–15% of relapses. Hydrophobic triterpene acids and hydrophilic lectins and viscotoxins from European mistletoe (Viscum album L.) demonstrate anticancer properties, but have not yet been investigated for Ewing sarcoma. Commercial Viscum album L. extracts are aqueous, excluding the insoluble triterpenes. We recreated a total mistletoe effect by combining an aqueous extract (viscum) and a triterpene extract (TT) solubilized with cyclodextrins. Ewing sarcoma cells were treated with viscum, TT and viscumTT in vitro, ex vivo and in vivo. In vitro and ex vivo treatment of Ewing sarcoma cells with viscum inhibited proliferation and induced apoptosis in a dose-dependent fashion, while viscumTT combination treatment generated a synergistic effect. Apoptosis occurred via intrinsic and extrinsic apoptotic pathways, evidenced by activation of both CASP8 and CASP9. We show that viscumTT treatment shifts the balance of apoptotic regulatory proteins towards apoptosis, mainly via CLSPN, MCL1, BIRC5 and XIAP downregulation. ViscumTT also demonstrated strong antitumor activity in a cell line- and patient-derived mouse model, and may be considered an adjuvant therapy option for pediatric patients with Ewing sarcoma.

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Survivin, a target to modulate the radiosensitivity of Ewing’s sarcoma

Cited by 41 publications

References 39 publications

Identification of a Novel SYK/c-MYC/MALAT1 Signaling Pathway and Its Potential Therapeutic Value in Ewing Sarcoma

Identification of a Novel SYK/c-MYC/MALAT1 Signaling Pathway and Its Potential Therapeutic Value in Ewing Sarcoma

Development of a radiosensitivity gene signature for patients with soft tissue sarcoma

Multiple Active Compounds from Viscum album L. Synergistically Converge to Promote Apoptosis in Ewing Sarcoma

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