Exploiting the Stemness and Chemoresistance Transcriptome of Ewing Sarcoma to Identify Candidate Therapeutic Targets and Drug-Repurposing Candidates
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Cell Culture
2.2. Western Blotting
2.3. Flow Cytometry
2.3.1. Cell Surface Expression of CD133
2.3.2. Co-Expression of ABCG1 and CD133
2.4. Self-Renewing Ability
2.5. Magnetically Activated Cell Sorting for the Enrichment of CD133-Positive Cells
2.6. RNA Expression of Markers of Pluripotency and Differentiation, the Wnt Signalling Pathway and ABC Transporter Proteins
2.7. Immunohistochemistry (IHC)
2.8. siRNA Knockdown of ABCG1
2.9. Apoptosis
2.10. Statistical Analyses
2.11. Identification of Candidate Drugs for Prioritised Molecular Targets
3. Results
3.1. ES Cell Lines Produce Spheroids and Clones from a Single Cell
3.2. CD133 Identifies Some Self-Renewing Drug-Resistant ES-CSCs
3.3. Gene Expression Profile of CD133 Low or Negative ES 3D Spheroids and 2D Cultures
3.4. Functional Role and Characterisation of ABCG1 in ES-CSCs
3.5. Identification of Candidate Drugs for ES-CSC Molecular Targets
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Cell Line | Clone or Spheroid Formation (%) | |||||
---|---|---|---|---|---|---|
Clone Formation in Soft Agar from a Single Cell | Ultra-Low Attachment Plate | |||||
1 Cell | 10 Cells | 100 Cells | 1000 Cells | 10,000 Cells | ||
A673 | 17 ±1 | 18 ± 5 | 88 ± 10 | 100 | 100 | 100 |
RD-ES | 17 ±1 | 5 ± 1 | 45 ± 13 | 100 | 100 | 100 |
SKES-1 | 29 ± 2 (p < 0.05) | 75 ± 7 (p < 0.05) | 98 ± 2 | 100 | 100 | 100 |
SK-N-MC | 12 ± 1 | 64 ± 1 | 97 ± 3 | 100 | 100 | 100 |
TC-32 | 7 ± 0.5 (p < 0.05) | 15 ± 3 | 93 ± 9 | 100 | 100 | 100 |
TTC 466 | 13 ± 1 | 45 ± 2 | 96 ± 6 | 100 | 100 | 100 |
Drug | Ewings Sarcoma Targets | Cancer Drug | BNFC approval | Off-Patent | Trial Count | Max Trial Phase | Trial Phase (Number of Trials in Phase) | Trial Status (Number of Trials in Status) | Cancer Type (Number of Trials in Cancer Type) | Trial Information for Phase 3 and Phase 4 trials (Trial Number, Phase, Status, Recruitment Status, Cancer Type) |
---|---|---|---|---|---|---|---|---|---|---|
Cabozantinib | KIT, RET, KDR, MET | Y | N | N | 6 | Phase 2 | Phase 1 (1), Phase 2 (5) | Recruiting (1), Active, not recruiting (3), Not yet recruiting (1), Other (1) | Multiple sarcomas, including Ewing’s (1), Mixed paediatric, including Ewing’s (3), Ewing’s or osteosarcoma (2) | NA |
Dasatinib | KIT, MAPK14, LYN, HSPA8, EPHB4, CSK, BCR, BTK, PDGFRB, EPHA2, SRC, ABL1 | Y | Y | Y | 2 | Phase 2 | Phase 1/2 (1), Phase 2 (1) | Active, not recruiting (1), Completed (1) | Mixed paediatric, including Ewing’s (1), Multiple sarcomas, including Ewing’s (1) | NA |
Decitabine | DNMT3B, DNMT1 | Y | N | Y | 1 | Phase 1 | Phase 1 (1) | Completed (1) | Mixed, including sarcomas (1) | NA |
Erdafitinib | KIT, KDR, PDGFRB, PDGFRA, CSF1R, RET, FGFR1 | Y | N | N | 1 | Phase 2 | Phase 2 (1) | Recruiting (1) | Mixed paediatric, including Ewing’s (1) | NA |
Imatinib | KIT, ABCB1, PDGFRB, ABL1, PDGFRA, CSF1R, NTRK1, RET, BCR | Y | Y | Y | 4 | Phase 2 | Phase 2 (4) | Completed (4) | Mixed, including sarcomas (1), Multiple sarcomas, including Ewing’s (1), Mixed paediatric, including Ewing’s (1), Ewing’s or DSRCT (1) | NI |
Lenvatinib | KIT, RET, PDGFRA, FGFR1, FLT4, KDR, FLT1 | Y | N | N | 1 | Phase 1/2 | Phase 1/2 (1) | Active, not recruiting (1) | Mixed paediatric, including Ewing’s (1) | NA |
Pazopanib | KIT, ITK, PDGFRB, PDGFRA, FLT4, KDR, FLT1 | Y | N | Y | 1 | Phase 2 | Phase 2 (1) | Completed (1) | Mixed paediatric, including Ewing’s (1) | NA |
Regorafenib | KIT, RET, ABL1, BRAF, EPHA2, NTRK1, TEK, FGFR1, PDGFRB, PDGFRA, FLT4, KDR, FLT1 | Y | N | N | 5 | Phase 2 | Phase 1 (1), Phase 1/2 (1), Phase 2 (2), Other (1) | Recruiting (4), Active, not recruiting (1) | Multiple sarcomas, including Ewing’s (3), Ewing’s or osteosarcoma (1), Mixed paediatric, including Ewing’s (1) | NA |
Sorafenib | KIT, ABCB1, FLT1, RET, FGFR1, PDGFRB, FLT3, KDR, FLT4, BRAF | Y | N | Unclear | 2 | Phase 2 | Phase 1 (1), Phase 2 (1) | Active, not recruiting (1), Completed (1) | Ewing’s or DSRCT (1), Mixed paediatric, including Ewing’s (1) | NA |
Sunitinib | KIT, ABCB1, PDGFRA, CSF1R, FLT3, FLT4, KDR, FLT1, PDGFRB | Y | N | Y | 2 | Phase 2 | Phase 1/2 (1), Phase 2 (1) | Ongoing (1), Completed (1) | Multiple sarcomas, including Ewing’s (1), Mixed, including sarcomas (1) | NA |
Temozolomide | ABCB1 | Y | Y | Y | 23 | Phase 3 | Phase 1 (10), Phase 1/2 (4), Phase 2 (8), Phase 3 (1) | Recruiting (8), Active, not recruiting (4), Completed (6), Not yet recruiting (2), Other (2), Terminated (1) | Mixed paediatric, including Ewing’s (6), Ewing’s (10), Mixed, including sarcomas (4), Ewing’s or DSRCT (1), Ewing’s or RMS (2) | NCT03495921 (Phase 3; Active, not recruiting)—Ewing sarcoma |
Aliskiren | ABCB1 | N | N | Y | 1 | Phase 2 | Phase 2 (1) | Recruiting (1) | Multiple cancer types (1) | NA |
Allopurinol | POU5F1 | N | Y | Y | 1 | Phase 1/2 | Phase 1/2 (1) | Not yet recruiting (1) | Lung (1) | NA |
Atorvastatin | ABCB1, NR1I3, HDAC2, AHR, DPP4, HMGCR | N | Y | Y | 16 | Phase 3 | Phase 1 (4), Phase 2 (6), Phase 2/3 (1), Phase 3 (5) | Recruiting (13), Ongoing (1), Not yet recruiting (2) | Multiple cancer types, Leukaemia (1), GI (4), Breast (8), Urological (3) | NCT03024684 (Phase 3; Recruiting)—Hepatocellular carcinoma, NCT03819101 (Phase 3; Recruiting)—Prostate, NCT03971019 (Phase 3; Recruiting)—Breast, NCT04601116 (Phase 3; Recruiting)—Breast, NCT04026230 (Phase 3; Recruiting)—Prostate |
Azithromycin | ABCC1 | N | Y | Y | 3 | Phase 2 | Phase 2 (3) | Ongoing (3) | Lymphoma (2), Breast (1) | NA |
Carvedilol | ABCB1, HIF1A, GJA1, VEGFA | N | Y | Y | 2 | Phase 2 | Phase 1 (1), Phase 2 (1) | Active, not recruiting (1), Not yet recruiting (1) | Urological (1), CNS (1) | NA |
Chlorpromazine | ABCB1 | N | N | Y | 3 | Phase 2 | Phase 1 (1), Phase 1/2 (1), Phase 2 (1) | Recruiting (2), Not yet recruiting (1) | GI (1), CNS (2) | NA |
Citalopram | ABCB1 | N | Y | Y | 1 | Phase 3 | Phase 3 (1) | Ongoing (1) | CNS (1) | 2013-004705-59 (Phase 3; Ongoing)—Glioblastoma |
Clarithromycin | ABCB1 | N | Y | Y | 18 | Phase 4 | Phase 1/2 (2), Phase 2 (10), Phase 3 (3), Phase 4 (1), Other (2) | Recruiting (8), Active, not recruiting (8), Not yet recruiting (1), Other (1) | Lymphoma (1), Other Haem-onc (15), Multiple cancer types (1), GI (1) | ChiCTR2100047608 (Phase 4; Recruiting)—Multiple Myeloma, NCT02575144 (Phase 3; Active, not recruiting)—Multiple Myeloma, NCT02516696 (Phase 3; Active, not recruiting)—Multiple Myeloma, NCT04287660 (Phase 3; Recruiting)—Multiple Myeloma |
Clopidogrel | ABCB1 | N | N | Y | 1 | Phase 1 | Phase 1 (1) | Recruiting (1) | Head and Neck (1) | NA |
Colchicine | ABCB1, TUBB | N | N | Y | 2 | Phase 2 | Phase 1 (1), Phase 2 (1) | Recruiting (2) | Urological, Multiple cancer types (1), GI (1) | NA |
Cyclosporine | ABCC1, ABCB1 | N | N | Y | 2 | Phase 2 | Phase 1 (1), Phase 2 (1) | Recruiting (1), Active, not recruiting (1) | Leukaemia (1), Other Haem-onc (1) | NA |
Deferoxamine | ABCB1 | N | N | Y | 4 | Phase 3 | Phase 1 (2), Phase 2 (1), Phase 3 (1) | Recruiting (3), Not yet recruiting (1) | Multiple cancer types (1), Breast (1), Leukaemia (1), GI (1) | IRCT20200313046756N2 (Phase 3; Pending)—Acute Myeloid Leukaemia |
Digoxin | ABCB1 | N | Y | Y | 2 | Phase 2 | Phase 1 (1), Phase 2 (1) | Recruiting (2) | GI (1), Multiple cancer types (1) | NA |
Disulfiram | ABCB1 | N | N | Y | 13 | Phase 2/3 | Phase 1 (4), Phase 1/2 (2), Phase 2 (6), Phase 2/3 (1) | Recruiting (7), Active, not recruiting (2), Ongoing (3), Not yet recruiting (1) | Multiple cancer types, GI (1), Soft-Tissue Sarcoma, Bone Sarcoma (1), CNS (3), Other Haem-onc (1), Urological (2), Multiple cancer types, Breast (1), GI (2), Breast (2) | NA |
Doxycycline | ABCB1 | N | Y | Y | 10 | Phase 2 | Phase 1 (1), Phase 2 (9) | Recruiting (4), Active, not recruiting (4), Ongoing (1), Not yet recruiting (1) | Urological (1), Lymphoma (3), Multiple cancer types (1), Breast, Gynaecological (1), Breast (1), GI (2), Head and Neck (1) | NA |
Fenofibrate | ABCB1, NR1I2 | N | Y | Y | 1 | Phase 2 | Phase 2 (1) | Recruiting (1) | CNS (1) | NA |
Fostamatinib | * | N | N | N | 2 | Phase 1 | Phase 1 (2) | Recruiting (2) | Gynaecological (1), Other Haem-onc, Leukaemia (1) | NA |
Indomethacin | ABCC1, PTGS2 | N | Y | Y | 5 | Phase 4 | Phase 1 (1), Phase 1/2 (1), Phase 2 (1), Phase 3 (1), Phase 4 (1) | Recruiting (2), Active, not recruiting (3) | Urological (2), Breast (1), Head and Neck (2) | ChiCTR2000038968 (Phase 4; Recruiting)—Prostate, NCT01265849 (Phase 3; Active, not recruiting)—Cancer of the oral cavity |
Itraconazole | ABCB1, ERBB2 | N | Y | Y | 15 | Phase 3 | Phase 1 (4), Phase 1/2 (2), Phase 2 (7), Phase 3 (1), Other (1) | Recruiting (9), Active, not recruiting (2), Completed (1), Not yet recruiting (1), Other (1), Suspended (1) | Leukaemia, Other Haem-onc (1), Lung (2), Multiple cancer types, Lymphoma, Leukaemia (1), follow-up continuing (1), Multiple cancer types (2), GI (4), Urological (1), Gynaecological (2), Skin (1) | NCT03458221 (Phase 3; Not yet recruiting)—Ovarian |
Ivermectin | ABCB1 | N | Y | Y | 2 | Phase 2 | Phase 2 (2) | Recruiting (1), Not yet recruiting (1) | Breast (1), Multiple cancer types (1) | NA |
Ketoconazole | ABCB1, NR1I3, NR1I2, AR | N | Y | Y | 4 | Phase 2 | Phase 1 (2), Phase 2 (2) | Recruiting (1), Active, not recruiting (2), Ongoing (1) | Urological (2), Breast, CNS (1), CNS (1) | NA |
Lansoprazole | ABCB1, MAPT | N | Y | Y | 3 | Phase 3 | Phase 2 (1), Phase 3 (2) | Recruiting (2), Active, not recruiting (1) | Breast (1), Lymphoma (1), GI (1) | NCT04874935 (Phase 3; Recruiting)—Breast, NCT03647072 (Phase 3; Recruiting)—Non-Hodgkin Lymphoma |
Levetiracetam | ABCB1 | N | Y | Y | 2 | Phase 2 | Phase 2 (1), Other (1) | Not yet recruiting (2) | CNS (2) | NA |
Losartan | ABCB1 | N | N | Y | 12 | Phase 3 | Phase 1 (4), Phase 2 (7), Phase 3 (1) | Recruiting (9), Active, not recruiting (1), Not yet recruiting (2) | Multiple cancer types (3), Bone Sarcoma (1), GI (7), Breast (1) | CTRI/2021/05/033482 (Phase 3; Not Yet Recruiting)—Pancreatic |
Lovastatin | ABCB1, HDAC2, HMGCR | N | N | Y | 1 | Other | Other (1) | Not yet recruiting (1) | GI (1) | NA |
Maprotiline | ABCB1 | N | N | Y | 1 | Phase 1 | Phase 1 (1) | Not yet recruiting (1) | CNS (1) | NA |
Mefloquine | ABCB1 | N | Y | Y | 1 | Phase 1 | Phase 1 (1) | Active, not recruiting (1) | CNS (1) | NA |
Miconazole | ABCB1, NR1I2 | N | Y | Y | 2 | Phase 2 | Phase 1 (1), Phase 2 (1) | Recruiting (2) | Multiple cancer types (2) | NA |
Midazolam | GABRB3, ABCB1 | N | Y | Y | 2 | Phase 2 | Phase 2 (2) | Recruiting (1), Not yet recruiting (1) | Urological (2) | NA |
Mifepristone | ABCB1, NR1I2, KLK3, NR3C1, PGR | N | N | Y | 2 | Phase 3 | Phase 2 (1), Phase 3 (1) | Active, not recruiting (1), Not yet recruiting (1) | Breast (2) | NCT05016349 (Phase 3; Not yet recruiting)—Breast |
Miltefosine | ABCB1 | N | N | Y | 2 | Phase 2 | Phase 2 (2) | Recruiting (1), Active, not recruiting (1) | Breast (1), Multiple cancer types (1) | NA |
Nelfinavir | ABCB1 | N | N | Y | 9 | Phase 3 | Phase 1 (2), Phase 1/2 (2), Phase 2 (3), Phase 3 (2) | Recruiting (5), Active, not recruiting (2), Ongoing (2) | Soft Tissue Sarcoma (1), Urological, Multiple cancer types (1), Gynaecological (3), Head and Neck (1), Other Haem-onc (1), GI (1), CNS (1) | NCT03256916 (Phase 3; Recruiting)—Advanced carcinoma of the cervix, CTRI/2017/08/009265 (Phase 3; Open to Recruitment)—Advanced carcinoma of the cervix |
Nicardipine | ABCB1 | N | N | Y | 1 | Other | Other (1) | Not yet recruiting (1) | CNS (1) | NA |
Omeprazole | ABCB1, AHR | N | Y | Y | 3 | Phase 2 | Phase 1 (2), Phase 2 (1) | Recruiting (2), Active, not recruiting (1) | Urological (1), Breast (1), GI (1) | NA |
Pantoprazole | ABCB1 | N | N | Y | 2 | Phase 2 | Phase 1/2 (1), Phase 2 (1) | Active, not recruiting (1), Not yet recruiting (1) | Head and Neck (1), Urological (1) | NA |
Phenytoin | POU5F1, SCN8A, SCN2A, SCN3A, NR1I2, SCN1A, SCN5A | N | Y | Y | 1 | Phase 2 | Phase 2 (1) | Recruiting (1) | Bone Sarcoma, Soft-Tissue Sarcoma (1) | NA |
Pravastatin | ABCB1, HDAC2, HMGCR | N | N | Y | 2 | Phase 4 | Phase 2 (1), Phase 4 (1) | Active, not recruiting (1), Not yet recruiting (1) | Leukaemia (1), Breast (1) | ChiCTR2000034035 (Phase 4; Pending)—Breast |
Propofol | GABRB3, ABCB1, SCN2A, SCN4A | N | Y | Y | 29 | Phase 4 | Phase 2 (1), Phase 3 (2), Phase 4 (7), Other (19) | Recruiting (17), Active, not recruiting (2), Ongoing (1), Not yet recruiting (9) | GI (6), Breast, GI (1), Multiple cancer types (7), Breast (5), Urological (3), Lung (6), CNS (1) | NCT01975064 (Phase 4; Recruiting)—Breast, colon, rectal, NCT05331911 (Phase 4; Not yet recruiting)—Liver, NCT04475705 (Phase 4; Recruiting)—Paediatric solid tumours, NCT05141877 (Phase 4; Not yet recruiting)—Brain tumour, NCT03034096 (Phase 4; Recruiting)—Adult cancer, NCT04513808 (Phase 3; Recruiting)—Oesophageal caner, ChiCTR2000040604 (Phase 4; Pending)—Non-small cell lung cancer, ACTRN12611000301965 (Phase 4; Not yet recruiting)—Breast, 2009-009114-40 (Phase 3; Ongoing)—Prostate |
Propranolol | ABCB1, EGFR, ADRB3 | N | N | Y | 19 | Phase 3 | Phase 1 (3), Phase 1/2 (1), Phase 2 (13), Phase 2/3 (1), Phase 3 (1) | Recruiting (10), Active, not recruiting (1), Not yet recruiting (7), Other (1) | GI (8), Urological (2), Soft Tissue Sarcoma (2), Gynaecological (1), Skin (3), Other (1), Multiple cancer types (2) | CTRI/2019/11/021924 (Phase 3; Not Yet Recruiting)—Ovarian |
Rifampicin | ABCB1, NR1I2 | N | Y | Y | 1 | Phase 1 | Phase 1 (1) | Recruiting (1) | Multiple cancer types, Lymphoma, Leukaemia (1) | NA |
Ritonavir | ABCC1, ABCB1, NR1I2 | N | Y | Y | 1 | Phase 1 | Phase 1 (1) | Recruiting (1) | Leukaemia, Lymphoma (1) | NA |
Sertraline | ABCB1, SLC29A4, SLC6A3 | N | Y | Y | 1 | Phase 1 | Phase 1 (1) | Recruiting (1) | Leukaemia (1) | NA |
Simvastatin | ABCB1, HDAC2, HMGCR | N | Y | Y | 18 | Phase 4 | Phase 1 (4), Phase 2 (11), Phase 3 (1), Phase 4 (2) | Recruiting (7), Active, not recruiting (3), Ongoing (3), Not yet recruiting (4), Suspended (1) | Breast (5), Other Haem-onc (1), Lung (3), Gynaecological (1), GI (6), Multiple cancer types (2) | ChiCTR2000034035 (Phase 4; Pending)—Breast, 2010-018491-24 (Phase 4; Ongoing)—Adults with bone metastasis, NCT03971019 (Phase 3; Recruiting)—Breast |
Sirolimus | ABCB1, MTOR | N | Y | Y | 28 | Phase 4 | Phase 1 (7), Phase 1/2 (4), Phase 2 (13), Phase 3 (2), Phase 4 (1), Other (1) | Recruiting (17), Active, not recruiting (7), Ongoing (3), Not yet recruiting (1) | Lung (2), Multiple cancer types, Lung (1), Multiple cancer types (6), Other (2), Soft-Tissue Sarcoma (3), Urological, Multiple cancer types (1), Bone Sarcoma, Soft Tissue Sarcoma (1), Gynaecological (1), Leukaemia (3), Endocrine (1), GI (3), CNS (1), Bone Sarcoma (2), Breast (1) | NCT04775173 (Phase 3; Recruiting)—Haemangioendothelioma, ChiCTR1900021896 (Phase 4; Recruiting)—Liver, NCT04736589 (Phase 3; Not yet recruiting)—Breast |
Valganciclovir | ABCB1 | N | Y | Y | 5 | Phase 2 | Phase 1/2 (2), Phase 2 (2), Other (1) | Recruiting (4), Not yet recruiting (1) | GI (1), Lymphoma (1), Head and Neck (1), CNS (1), Multiple cancer types (1) | NA |
Verapamil | ABCC1, ABCB1 | N | N | Y | 1 | Phase 1 | Phase 1 (1) | Active, not recruiting (1) | Lymphoma (1) | NA |
Warfarin | ABCB1, AXL, NR1I2 | N | N | Y | 1 | Phase 1 | Phase 1 (1) | Recruiting (1) | GI (1) | NA |
Zidovudine | ABCC1, ABCB1, TERT | N | Y | Y | 1 | Phase 2 | Phase 2 (1) | Recruiting (1) | Leukaemia (1) | NA |
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Roundhill, E.A.; Pantziarka, P.; Liddle, D.E.; Shaw, L.A.; Albadrani, G.; Burchill, S.A. Exploiting the Stemness and Chemoresistance Transcriptome of Ewing Sarcoma to Identify Candidate Therapeutic Targets and Drug-Repurposing Candidates. Cancers 2023, 15, 769. https://doi.org/10.3390/cancers15030769
Roundhill EA, Pantziarka P, Liddle DE, Shaw LA, Albadrani G, Burchill SA. Exploiting the Stemness and Chemoresistance Transcriptome of Ewing Sarcoma to Identify Candidate Therapeutic Targets and Drug-Repurposing Candidates. Cancers. 2023; 15(3):769. https://doi.org/10.3390/cancers15030769
Chicago/Turabian StyleRoundhill, Elizabeth Ann, Pan Pantziarka, Danielle E. Liddle, Lucy A. Shaw, Ghadeer Albadrani, and Susan Ann Burchill. 2023. "Exploiting the Stemness and Chemoresistance Transcriptome of Ewing Sarcoma to Identify Candidate Therapeutic Targets and Drug-Repurposing Candidates" Cancers 15, no. 3: 769. https://doi.org/10.3390/cancers15030769