Novel Targeted Therapeutic Strategies for Ewing Sarcoma
Abstract
:Simple Summary
Abstract
1. Introduction
2. General Consideration: Hallmarks of Cancer
3. Molecular Targets for ES Therapy
3.1. Targeting of ES Pressure on Adhesion, Migration, and Invasion
3.2. Targeting of Ewing Sarcoma Cells with a Focus on Proliferation, Cell Differentiation, and Cell Survival
3.3. Targeting of ES: Induction of Apoptosis and Cell Cycle Arrest
4. Current Clinical Trials
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviation
CD99 | cluster of differentiation 99 |
EMT | epithelial to mesenchymal transition |
ERBB4 | Erb-B2 Receptor Tyrosine Kinase 4 |
ES | Ewing sarcoma |
ESFT | Ewing sarcoma family tumors |
EZH2 | Enhancer Of Zeste 2 Polycomb Repressive Complex 2 Subunit |
GDF6 | growth and differentiation factor 6 |
FET | family of genes, Fused in sarcoma, Ewing sarcoma breakpoint region 1, TATA-box binding protein associated factor 15 |
GLI1 | glioma-associated oncogene 1 |
IGF-1 | Insulin-like growth factor |
IGF-1R | insulin-like growth factor 1 receptor |
LDH | lactate dehydrogenase |
lncRNAs | long non-coding RNAs |
MAPK | Mitogen-Activated Protein Kinase |
MET | mesenchymal to epithelial transition |
MMP9 | metalloproteinase type 9 |
MRTFB | of Myocardin-related transcription factor B |
NAMPT | nicotinamide phosphoribosyl transferase |
NCAM | neural cell adhesion molecule |
PAPP-A | Pregnancy-associated plasma protein A |
PARP | Poly (ADP-ribose) polymerase |
PDGF | Platelet-derived growth factor |
PHGDH | 3-phosphoglycerate dehydrogenase |
PI3K | Phosphoinositide 3-kinases |
ROCK | Rho-associated coiled-coil kinase |
RhoA | Ras homolog family member A |
SHH | Sonic Hedgehog pathway |
SOX2 | SRY-Box Transcription Factor 2 |
SRBCT | Small Round Blue Cell Tumors |
TEAD | TEA domain family member 1 |
TNF | tumor necrosis factor |
mTOR | mammalian target of rapamycin |
TRAIL | TNF-Related Apoptosis Inducing Ligand |
PNET | Primitive neuroectodermal tumor |
VEGF-A | Vascular endothelial growth factor A |
YAP | Yes-associated protein. |
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Targetable Molecules | Main Pathways | Tumor Effects |
---|---|---|
CD99 | IGF-1R and RAS-Rac1 signaling | Induces caspase-independent cell death, endocytosis, cell aggregation, micropinocytosis, cell adhesion, migration, invasion, metastasis, differentiation |
GDF6 | GDF6 prodomain signaling pathway | Cell proliferation, tumor growth, differentiation, apoptosis |
E-cadherin | MAPK Pathway | Anchorage-independent growth and spheroid formation, cell-cell adhesion |
Endoglin | TGFβ signaling | Tumor cell plasticity, patient survival, invasion, anchorage-independent growth, progression of aggressive tumors |
EZH2 | Epigenetic | Cell differentiation, phenotypic heterogeneity, self-renewal |
GLI1 | Sonic Hedgehog (SHH) pathway | Cell proliferation, cell cycle control, apoptosis, cell viability, metastasis, invasion, migration, clonogenicity |
PDGF family members | PDGF pathway | Self-renewal, invasion, chemotherapy resistance, primary tumor growth, metastasis, drug resistance, poor clinical outcome |
ROCK2 | RhoA-ROCK pathway | Migration, invasion, proliferation, clonogenic capacity, tumor growth |
YAP proteins | YAP/TAZ pathway, Hippo signaling, WNT/β-catenin signaling | Migration, cell proliferation, metastasis, anchorage-independent colony formation |
PAPP-A | IGF signaling | Cell proliferation, migration, cell survival, tumor growth, invasion, metastasis |
PARP family | DNA repair, replication | Apoptosis |
TRAIL | TRAIL-pathway | Induces caspase-independent cell death, apoptosis |
ATR/CHK1 | ATR-CHK1 pathway | Cell cycle regulation, cell cycle arrest |
LDH | aerobic glycolysis | Cell proliferation, apoptosis, tumor growth, cell survival |
PHGDH | Serine synthesis | Cell proliferation |
lncRNA SOX2 | WNT/β-catenin signaling | Cell proliferation, invasion, apoptosis, tumor growth |
lncRNA TUG1 | TUG-miR-145-5p-TRPC6 pathway | Cell proliferation, migration, invasion |
S.N. | Number | Number of Patients | Disease | Drug/Target | Results |
---|---|---|---|---|---|
1 | NCT04129151 | 18 | Ewing Sarcoma Recurrent | Palbociclib/CDK4 and CDK6 Ganitumab/IGF-1R | Active |
2 | NCT02546544 | 16 | Relapsed Ewing Sarcoma Refractory Ewing Sarcoma | Linsitinib/IGF-1R | Disease progression, limited therapeutical effect |
3 | NCT00949325 | 24 | Soft Tissue and Bone Sarcoma | Temsirolimus/mTOR Doxorubicin/topoisomerase II | The response rate was 53%, found a correlation between inhibition of mTOR and therapeutical effect 10.1186/s13569-018-0107-9 |
4 | NCT00987636 | 907 | Ewing sarcoma | Zoledronic acid/osteoclast apoptosis Busulfan/guanine N7 Treosulfan/guanine N7 Melphalan/guanine N7 | BuMel treatment was more successful than standard chemotherapy -vincristine, dactinomycin, and ifosfamide (VAI) |
5 | NCT00618813 | 35 | Ewing Sarcoma | Radiation therapy therapeutic conventional surgery etoposide/topoisomerase II ifosfamide/DNA doxorubicin hydrochloride/topoisomerase II cyclophosphamide/guanine N7 vincristine sulfate/tubulin topotecan hydrochloride/topoisomerase I filgrastim/Granulocyte | No incidence of death was recorded in 37 weeks of treatment |
6 | NCT00516295 | 7 | Ewing Sarcoma of Bone Extraosseous Ewing Sarcoma Peripheral Primitive Neuroectodermal Tumor Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor | Topotecan hydrochloride/topoisomerase I cyclophosphamide/guanine N7 vincristine sulfate/tubulin bevacizumab/VEGF-A | Days of event free survival—442 |
7 | NCT00470275 | 10 | Recurrent or Refractory Ewing Sarcoma | Cytarabine/DNA | Lack of efficacy |
8 | NCT02657005 | 45 | Relapsed or Refractory Ewing Sarcoma | TK216/EWS-FLI1 | Active |
9 | NCT00061893 | 38 | Ewing Sarcoma Family of Tumors | Radiation therapy conventional surgery etoposide/topoisomerase II ifosfamide/DNA doxorubicin hydrochloride/topoisomerase II cyclophosphamide/guanine N7 vincristine sulfate/tubulin topotecan hydrochloride/topoisomerase I filgrastim/granulocyte vinblastine sulfate/tubulin MESNA/urotoxic metabolites | 24-month event free survival was 35%: 71% for the seven with isolated pulmonary metastases, 26% for all others. |
10 | NCT02511132 | 22 | Ewing Sarcoma | Vigil/TGF-β Temozolomide/guanine Irinotecan/topoisomerase I | 1 case report of complete response to therapy |
11 | NCT01583543 | 12 | Recurrent/Metastatic Ewing’s Sarcoma | Olaparib/PARP | No significant responses or durable disease control was seen |
12 | NCT01331135 | 18 | Ewing sarcoma, osteosarcoma, malignant peripheral nerve sheath tumor, rhabdoid tumor, retinoblastoma | Sirolimus/mTOR | The combination of sirolimus with metronomic chemotherapy is well tolerated in children. A phase II trial of this combination is ongoing. |
13 | NCT00428272 | 24 | Ewing Sarcoma Osteosarcoma Neuroblastoma Rhabdomyosarcoma | Lexatumumab/TRAIL-2R | The drug seems to mediate some clinical activity in pediatric solid tumors and may work with radiation to enhance antitumor effects. |
14 | NCT02306161 | 312 | Metastatic Ewing Sarcoma Metastatic Malignant Neoplasm in the Bone Metastatic Malignant Neoplasm in the Bone Marrow Metastatic Malignant Neoplasm in the Lung Metastatic Peripheral Primitive Neuroectodermal Tumor of Bone Peripheral Primitive Neuroectodermal Tumor of Soft Tissues | Cyclophosphamide/guanine N7 Doxorubicin/topoisomerase II Etoposide/topoisomerase II Ganitumab/IGevent-freeF-1R Ifosfamide/DNA Vincristine/tubulin | Active |
15 | NCT04067115 | 45 | Ewing Sarcoma | Trabectedin/guanine N2 Irinotecan/topoisomerase I | Recruiting |
16 | NCT00070109 | 50 | Rhabdomyosarcoma Recurrent Childhood Rhabdomyosarcoma Recurrent Childhood Soft Tissue Sarcoma Recurrent Ewing Sarcoma Peripheral Primitive Neuroectodermal Tumor | Trabectedin/guanine N2 | |
17 | NCT03600649 | 50 | Ewing Sarcoma Myxoid Liposarcoma Sarcoma, Soft Tissue Desmoplastic Small Round Cell Tumor Extraskeletal Myxoid Chondrosarcoma Angiomatoid Fibrous Histiocytoma Clear Cell Sarcoma Primary Pulmonary Myxoid Sarcoma Myoepithelial Tumor Sclerosing Epithelioid Fibrosarcoma Fibromyxoid Tumor | Cyclophosphamide/guanine N7 Topotecan/topoisomerase I Seclidemstat/LSD1 | Recruiting |
18 | NCT03491371 | 56 | Osteosarcoma Ewing sarcoma Chondrosarcoma Soft tissue sarcoma | Methylsulfonic apatinib/VEGFR-2 | No data |
19 | NCT04690725 | 29 | Osteosarcoma Ewing sarcoma Chondrosarcoma | TQB3525/PI 3-kinases | Active |
20 | NCT01610570 | 8 | Ewing Sarcoma Sarcoma | Mithramycin/EWS-FLI1 | The trial was closed to enrollment, due to inability to safely achieve the desired mithramycin exposure |
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Fayzullina, D.; Tsibulnikov, S.; Stempen, M.; Schroeder, B.A.; Kumar, N.; Kharwar, R.K.; Acharya, A.; Timashev, P.; Ulasov, I. Novel Targeted Therapeutic Strategies for Ewing Sarcoma. Cancers 2022, 14, 1988. https://doi.org/10.3390/cancers14081988
Fayzullina D, Tsibulnikov S, Stempen M, Schroeder BA, Kumar N, Kharwar RK, Acharya A, Timashev P, Ulasov I. Novel Targeted Therapeutic Strategies for Ewing Sarcoma. Cancers. 2022; 14(8):1988. https://doi.org/10.3390/cancers14081988
Chicago/Turabian StyleFayzullina, Daria, Sergey Tsibulnikov, Mikhail Stempen, Brett A. Schroeder, Naveen Kumar, Rajesh Kumar Kharwar, Arbind Acharya, Peter Timashev, and Ilya Ulasov. 2022. "Novel Targeted Therapeutic Strategies for Ewing Sarcoma" Cancers 14, no. 8: 1988. https://doi.org/10.3390/cancers14081988