Disease Information

General Information of the Disease (ID: DIS00063)

• Name: Ewing sarcoma
• ICD: ICD-11: 2B52

Type(s) of Resistant Mechanism of This Disease

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 4 drug(s) in total

Doxorubicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-125b [1]

• Resistant Disease: Ewing sarcoma [ICD-11: 2B52.0]
• Resistant Drug: Doxorubicin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: miR125b-p53/BAKT signaling pathway; Activation; hsa05206
• In Vitro Model: RD-ES cells; Bones; Homo sapiens (Human); CVCL_2169
• In Vitro Model: Sk-ES cells; Bones; Homo sapiens (Human); CVCL_0627
• In Vitro Model: Sk-N-MC cells; Bones; Homo sapiens (Human); CVCL_0530
• In Vitro Model: TC-71 cells; Bones; Homo sapiens (Human); CVCL_2213
• In Vitro Model: VH-64 cells; Bones; Homo sapiens (Human); CVCL_9672
• In Vitro Model: WE-68 cells; Bones; Homo sapiens (Human); CVCL_9717
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Celltiter-glo luminescent cell viability assay
• Mechanism Description: miR-125b led to the development of chemoresistance by suppressing the expression of p53 and Bak, and repression of miR-125b sensitized EWS cells to apoptosis induced by treatment with various cytotoxic drugs.

Key Molecule: hsa-miR-34a [2]

• Resistant Disease: Ewing sarcoma [ICD-11: 2B52.0]
• Resistant Drug: Doxorubicin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Experiment for Molecule Alteration: Microarray analysis; qRT-PCR; Northern blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Results were particularly robust for miR-34a, which appeared associated with either event-free or overall survival and emerged as a significant predictor also after multivariate analysis

Key Molecule: hsa-let-7c [3]

• Resistant Disease: Ewing sarcoma [ICD-11: 2B52.0]
• Resistant Drug: Doxorubicin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: VH-64 cells; Bones; Homo sapiens (Human); CVCL_9672
• In Vitro Model: Sk-N-MC cells; Bones; Homo sapiens (Human); CVCL_0530
• In Vitro Model: RD-ES cells; Bones; Homo sapiens (Human); CVCL_2169
• In Vitro Model: Sk-ES cells; Bones; Homo sapiens (Human); CVCL_0627
• In Vitro Model: TC-71 cells; Bones; Homo sapiens (Human); CVCL_2213
• Experiment for Molecule Alteration: qRT-PCR; Western blot
• Experiment for Drug Resistance: Chemosensitivity assay
• Mechanism Description: The expression of hsa-let-7c is decreased.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Cellular tumor antigen p53 (TP53) [1]

• Resistant Disease: Ewing sarcoma [ICD-11: 2B52.0]
• Resistant Drug: Doxorubicin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: miR125b-p53/BAKT signaling pathway; Activation; hsa05206
• In Vitro Model: RD-ES cells; Bones; Homo sapiens (Human); CVCL_2169
• In Vitro Model: Sk-ES cells; Bones; Homo sapiens (Human); CVCL_0627
• In Vitro Model: Sk-N-MC cells; Bones; Homo sapiens (Human); CVCL_0530
• In Vitro Model: TC-71 cells; Bones; Homo sapiens (Human); CVCL_2213
• In Vitro Model: VH-64 cells; Bones; Homo sapiens (Human); CVCL_9672
• In Vitro Model: WE-68 cells; Bones; Homo sapiens (Human); CVCL_9717
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Celltiter-glo luminescent cell viability assay
• Mechanism Description: miR-125b led to the development of chemoresistance by suppressing the expression of p53 and Bak, and repression of miR-125b sensitized EWS cells to apoptosis induced by treatment with various cytotoxic drugs.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-34 [4]

• Sensitive Disease: Ewing sarcoma [ICD-11: 2B52.0]
• Sensitive Drug: Doxorubicin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: Sk-ES-1 cells; Bone; Homo sapiens (Human); CVCL_0627
• In Vitro Model: Sk-N-MC cells; Bones; Homo sapiens (Human); CVCL_0530
• In Vitro Model: TC-71 cells; Bones; Homo sapiens (Human); CVCL_2213
• In Vitro Model: IOR/CAR cells; Sarcoma; Homo sapiens (Human); CVCL_H725
• Experiment for Molecule Alteration: qRT-PCR; Northern blotting analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Increased chemo-sensitivity and decreased aggressiveness of EWS cells after enforced expression of miR-34a.

Etoposide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-125b [1]

• Resistant Disease: Ewing sarcoma [ICD-11: 2B52.0]
• Resistant Drug: Etoposide
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: miR125b-p53/BAKT signaling pathway; Activation; hsa05206
• In Vitro Model: RD-ES cells; Bones; Homo sapiens (Human); CVCL_2169
• In Vitro Model: Sk-ES cells; Bones; Homo sapiens (Human); CVCL_0627
• In Vitro Model: Sk-N-MC cells; Bones; Homo sapiens (Human); CVCL_0530
• In Vitro Model: TC-71 cells; Bones; Homo sapiens (Human); CVCL_2213
• In Vitro Model: VH-64 cells; Bones; Homo sapiens (Human); CVCL_9672
• In Vitro Model: WE-68 cells; Bones; Homo sapiens (Human); CVCL_9717
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Celltiter-glo luminescent cell viability assay
• Mechanism Description: miR-125b led to the development of chemoresistance by suppressing the expression of p53 and Bak, and repression of miR-125b sensitized EWS cells to apoptosis induced by treatment with various cytotoxic drugs.

Key Molecule: hsa-miR-708 [5]

• Resistant Disease: Ewing sarcoma [ICD-11: 2B52.0]
• Resistant Drug: Etoposide
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: EWS/FLI1 /miR-708/EYA3; Regulation; N.A.
• Experiment for Molecule Alteration: Western blot; RT-PCR; Luciferase reporter assays
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: We further show that EWS/FLI1 mediates upregulation of EYA3 via repression of miR-708, a miRNA that targets the EYA3 3'-untranslated region, rather than by binding the EYA3 promoter directly

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Cellular tumor antigen p53 (TP53) [1]

• Resistant Disease: Ewing sarcoma [ICD-11: 2B52.0]
• Resistant Drug: Etoposide
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: miR125b-p53/BAKT signaling pathway; Activation; hsa05206
• In Vitro Model: RD-ES cells; Bones; Homo sapiens (Human); CVCL_2169
• In Vitro Model: Sk-ES cells; Bones; Homo sapiens (Human); CVCL_0627
• In Vitro Model: Sk-N-MC cells; Bones; Homo sapiens (Human); CVCL_0530
• In Vitro Model: TC-71 cells; Bones; Homo sapiens (Human); CVCL_2213
• In Vitro Model: VH-64 cells; Bones; Homo sapiens (Human); CVCL_9672
• In Vitro Model: WE-68 cells; Bones; Homo sapiens (Human); CVCL_9717
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Celltiter-glo luminescent cell viability assay
• Mechanism Description: miR-125b led to the development of chemoresistance by suppressing the expression of p53 and Bak, and repression of miR-125b sensitized EWS cells to apoptosis induced by treatment with various cytotoxic drugs.

Teprotumumab

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Protein-tyrosine phosphatase delta (PTPRD) [6]

• Sensitive Disease: Ewing sarcoma [ICD-11: 2B52.0]
• Sensitive Drug: Teprotumumab
• Molecule Alteration: Missense mutation; p.V253I (c.757G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ewing sarcoma tissue; N.A.
• Experiment for Molecule Alteration: DNA sequencing assay
• Mechanism Description: The missense mutation p.V253I (c.757G>A) in gene PTPRD cause the sensitivity of Teprotumumab by unusual activation of pro-survival pathway

Vincristine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-125b [1]

• Resistant Disease: Ewing sarcoma [ICD-11: 2B52.0]
• Resistant Drug: Vincristine
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: miR125b-p53/BAKT signaling pathway; Activation; hsa05206
• In Vitro Model: RD-ES cells; Bones; Homo sapiens (Human); CVCL_2169
• In Vitro Model: Sk-ES cells; Bones; Homo sapiens (Human); CVCL_0627
• In Vitro Model: Sk-N-MC cells; Bones; Homo sapiens (Human); CVCL_0530
• In Vitro Model: TC-71 cells; Bones; Homo sapiens (Human); CVCL_2213
• In Vitro Model: VH-64 cells; Bones; Homo sapiens (Human); CVCL_9672
• In Vitro Model: WE-68 cells; Bones; Homo sapiens (Human); CVCL_9717
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Celltiter-glo luminescent cell viability assay
• Mechanism Description: miR-125b led to the development of chemoresistance by suppressing the expression of p53 and Bak, and repression of miR-125b sensitized EWS cells to apoptosis induced by treatment with various cytotoxic drugs.

Key Molecule: hsa-miR-34a [2]

• Resistant Disease: Ewing sarcoma [ICD-11: 2B52.0]
• Resistant Drug: Vincristine
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Experiment for Molecule Alteration: Microarray analysis; qRT-PCR; Northern blot analysis; Immunoprecipitation; Luciferase assays
• Experiment for Drug Resistance: Flow cytometry assay; Chemosensitivity assays
• Mechanism Description: Results were particularly robust for miR-34a, which appeared associated with either event-free or overall survival and emerged as a significant predictor also after multivariate analysis

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Cellular tumor antigen p53 (TP53) [1]

• Resistant Disease: Ewing sarcoma [ICD-11: 2B52.0]
• Resistant Drug: Vincristine
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: miR125b-p53/BAKT signaling pathway; Activation; hsa05206
• In Vitro Model: RD-ES cells; Bones; Homo sapiens (Human); CVCL_2169
• In Vitro Model: Sk-ES cells; Bones; Homo sapiens (Human); CVCL_0627
• In Vitro Model: Sk-N-MC cells; Bones; Homo sapiens (Human); CVCL_0530
• In Vitro Model: TC-71 cells; Bones; Homo sapiens (Human); CVCL_2213
• In Vitro Model: VH-64 cells; Bones; Homo sapiens (Human); CVCL_9672
• In Vitro Model: WE-68 cells; Bones; Homo sapiens (Human); CVCL_9717
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Celltiter-glo luminescent cell viability assay
• Mechanism Description: miR-125b led to the development of chemoresistance by suppressing the expression of p53 and Bak, and repression of miR-125b sensitized EWS cells to apoptosis induced by treatment with various cytotoxic drugs.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-34 [4]

• Sensitive Disease: Ewing sarcoma [ICD-11: 2B52.0]
• Sensitive Drug: Vincristine
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• In Vitro Model: Sk-ES-1 cells; Bone; Homo sapiens (Human); CVCL_0627
• In Vitro Model: Sk-N-MC cells; Bones; Homo sapiens (Human); CVCL_0530
• In Vitro Model: TC-71 cells; Bones; Homo sapiens (Human); CVCL_2213
• In Vitro Model: IOR/CAR cells; Sarcoma; Homo sapiens (Human); CVCL_H725
• Experiment for Molecule Alteration: qRT-PCR; Northern blotting analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Increased chemo-sensitivity and decreased aggressiveness of EWS cells after enforced expression of miR-34a.

Clinical Trial Drug(s) 1 drug(s) in total

Cixutumumab

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Protein-tyrosine phosphatase delta (PTPRD) [6]

• Sensitive Disease: Ewing sarcoma [ICD-11: 2B52.0]
• Sensitive Drug: Cixutumumab
• Molecule Alteration: Missense mutation; p.V253I (c.757G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ewing sarcoma tissue; N.A.
• Experiment for Molecule Alteration: DNA sequencing assay
• Mechanism Description: The missense mutation p.V253I (c.757G>A) in gene PTPRD cause the sensitivity of Cixutumumab by unusual activation of pro-survival pathway

Investigative 1 drug(s) in total

Mafosfamide Sodium Salt

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-125b-1 [3]

• Resistant Disease: Ewing sarcoma [ICD-11: 2B52.0]
• Resistant Drug: Mafosfamide Sodium Salt
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: VH-64 cells; Bones; Homo sapiens (Human); CVCL_9672
• In Vitro Model: Sk-N-MC cells; Bones; Homo sapiens (Human); CVCL_0530
• In Vitro Model: RD-ES cells; Bones; Homo sapiens (Human); CVCL_2169
• In Vitro Model: Sk-ES cells; Bones; Homo sapiens (Human); CVCL_0627
• In Vitro Model: TC-71 cells; Bones; Homo sapiens (Human); CVCL_2213
• Experiment for Molecule Alteration: qRT-PCR; Western blot
• Experiment for Drug Resistance: Chemosensitivity assay
• Mechanism Description: We found miR-125b to be upregulated in two different Dox-resistant EWS cell lines. The upregulation of miR-125b was also confirmed in the EWS tumors having survived chemotherapy regimen which includes doxorubicin. When miR-125b was knocked down in EWS cells, both the Dox-resistant and parental cells showed an enhanced sensitivity to doxorubicin, which was associated with the upregulation of the pro-apoptotic molecules, p53 and Bak. Inversely, the overexpression of miR-125b in parental EWS cells resulted in enhanced drug resistance, not only to doxorubicin, but also to etoposide and vincristine.

Investigative Drug(s) 1 drug(s) in total

YK-4-279

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Hepatocellular carcinoma up-regulated long non-coding RNA (HULC) [7]

• Resistant Disease: Ewing sarcoma [ICD-11: 2B52.0]
• Resistant Drug: YK-4-279
• Molecule Alteration: Up-regulation; Interaction
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: LAP-35 cells; Bone marrow; Homo sapiens (Human); CVCL_A096
• Experiment for Molecule Alteration: RNA-seq assay
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: Ewing sarcomas (ES) characterized by in frame chromosomal translocations giving rise to chimeric transcription factors, such as EWS-FLI1. High levels of HULC correlate with ES aggressiveness, whereas HULC depletion reduces ES cell growth.

References

• Ref 1: miR-125b develops chemoresistance in Ewing sarcoma/primitive neuroectodermal tumor. Cancer Cell Int. 2013 Mar 4;13(1):21. doi: 10.1186/1475-2867-13-21.
• Ref 2: PF-04691502, a potent and selective oral inhibitor of PI3K and mTOR kinases with antitumor activityMol Cancer Ther. 2011 Nov;10(11):2189-99. doi: 10.1158/1535-7163.MCT-11-0185. Epub 2011 Jul 12.
• Ref 3: VS-5584, a novel and highly selective PI3K/mTOR kinase inhibitor for the treatment of cancerMol Cancer Ther. 2013 Feb;12(2):151-61. doi: 10.1158/1535-7163.MCT-12-0466. Epub 2012 Dec 27.
• Ref 4: miR-34a predicts survival of Ewing's sarcoma patients and directly influences cell chemo-sensitivity and malignancy. J Pathol. 2012 Apr;226(5):796-805. doi: 10.1002/path.3007.
• Ref 5: Protein kinase C inhibitor AEB071 targets ocular melanoma harboring GNAQ mutations via effects on the PKC/Erk1/2 and PKC/NF-kB pathwaysMol Cancer Ther. 2012 Sep;11(9):1905-14. doi: 10.1158/1535-7163.MCT-12-0121. Epub 2012 May 31.
• Ref 6: Germline PTPRD mutations in Ewing sarcoma: biologic and clinical implicationsOncotarget. 2013 Jun;4(6):884-9. doi: 10.18632/oncotarget.1021.
• Ref 7: Small molecule inhibition of Ewing sarcoma cell growth via targeting the long non coding RNA HULCCancer Lett. 2020 Jan 28;469:111-123. doi: 10.1016/j.canlet.2019.10.026. Epub 2019 Oct 19.