Emerging novel agents for patients with advanced Ewing sarcoma: a report from the Children's Oncology Group (COG) New Agents for Ewing Sarcoma Task Force

doi:10.12688/f1000research.18139.1

Review

. 2019 Apr 15:8:F1000 Faculty Rev-493.

doi: 10.12688/f1000research.18139.1. eCollection 2019.

Emerging novel agents for patients with advanced Ewing sarcoma: a report from the Children's Oncology Group (COG) New Agents for Ewing Sarcoma Task Force

Kelly Bailey^#¹, Carrye Cost^#², Ian Davis³, Julia Glade-Bender⁴, Patrick Grohar⁵, Peter Houghton⁶, Michael Isakoff⁷, Elizabeth Stewart⁸, Nadia Laack⁹, Jason Yustein¹⁰, Damon Reed^{11

12}, Katherine Janeway¹³, Richard Gorlick¹⁴, Stephen Lessnick^#^{15

16}, Steven DuBois^#¹³, Pooja Hingorani^#¹⁷

Affiliations

¹ Division of Pediatric Hematology/Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
² Center for Cancer and Blood Disorders, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA.
³ Departments of Pediatrics and Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
⁴ Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
⁵ Departement of Pediatrics, Van Andel Institute, Helen De Vos Children's Hospital and Michigan State University, Grand Rapids, MI, USA.
⁶ Greehey Children's Cancer Research Institute, University of Texas Health Science Center, San Antonio, TX, USA.
⁷ Center for Cancer and Blood Disorders, Connecticut Children's Medical Center, Hartford, CT, USA.
⁸ Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.
⁹ Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA.
¹⁰ The Faris D. Virani Ewing Sarcoma Center at the Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX, USA.
¹¹ AYA Program, Moffitt Cancer Center, Tampa, FL, USA.
¹² Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA.
¹³ Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, MA, USA.
¹⁴ Division of Pediatrics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁵ Center for Childhood Cancer and Blood Diseases, Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
¹⁶ Division of Pediatric Hematology/Oncology/Bone Marrow Transplantation, The Ohio State University College of Medicine, Columbus, OH, USA.
¹⁷ Center for Cancer and Blood Disorders, Phoenix Children's Hospital, Phoenix, AZ, USA.

^# Contributed equally.

PMID: 31031965
PMCID: PMC6468706
DOI: 10.12688/f1000research.18139.1

Review

Emerging novel agents for patients with advanced Ewing sarcoma: a report from the Children's Oncology Group (COG) New Agents for Ewing Sarcoma Task Force

Kelly Bailey et al. F1000Res. 2019.

. 2019 Apr 15:8:F1000 Faculty Rev-493.

doi: 10.12688/f1000research.18139.1. eCollection 2019.

Authors

Affiliations

¹ Division of Pediatric Hematology/Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
² Center for Cancer and Blood Disorders, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA.
³ Departments of Pediatrics and Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
⁴ Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
⁵ Departement of Pediatrics, Van Andel Institute, Helen De Vos Children's Hospital and Michigan State University, Grand Rapids, MI, USA.
⁶ Greehey Children's Cancer Research Institute, University of Texas Health Science Center, San Antonio, TX, USA.
⁷ Center for Cancer and Blood Disorders, Connecticut Children's Medical Center, Hartford, CT, USA.
⁸ Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.
⁹ Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA.
¹⁰ The Faris D. Virani Ewing Sarcoma Center at the Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX, USA.
¹¹ AYA Program, Moffitt Cancer Center, Tampa, FL, USA.
¹² Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA.
¹³ Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, MA, USA.
¹⁴ Division of Pediatrics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁵ Center for Childhood Cancer and Blood Diseases, Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
¹⁶ Division of Pediatric Hematology/Oncology/Bone Marrow Transplantation, The Ohio State University College of Medicine, Columbus, OH, USA.
¹⁷ Center for Cancer and Blood Disorders, Phoenix Children's Hospital, Phoenix, AZ, USA.

^# Contributed equally.

PMID: 31031965
PMCID: PMC6468706
DOI: 10.12688/f1000research.18139.1

Abstract

Ewing sarcoma is a small round blue cell malignancy arising from bone or soft tissue and most commonly affects adolescents and young adults. Metastatic and relapsed Ewing sarcoma have poor outcomes and recurrences remain common. Owing to the poor outcomes associated with advanced disease and the need for a clear research strategy, the Children's Oncology Group Bone Tumor Committee formed the New Agents for Ewing Sarcoma Task Force to bring together experts in the field to evaluate and prioritize new agents for incorporation into clinical trials. This group's mission was to evaluate scientific and clinical challenges in moving new agents forward and to recommend agents and trial designs to the Bone Tumor Committee. The task force generated a framework for vetting prospective agents that included critical evaluation of each drug by using both clinical and non-clinical parameters. Representative appraisal of agents of highest priority, including eribulin, dinutuximab, cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, anti-angiogenic tyrosine kinase inhibitors, and poly-ADP-ribose polymerase (PARP) inhibitors, is described. The task force continues to analyze new compounds by using the paradigm established.

Keywords: Ewing sarcoma; clinical trials; metastasis; relapse; therapy.

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Conflict of interest statement

No competing interests were disclosed.No competing interests were disclosed.No competing interests were disclosed.No competing interests were disclosed.

Figures

**Figure 1.. Paradigm for evaluation new agents for Ewing sarcoma.**
Task force members proposed agents or targets (detailed in Table 1). These proposals were then each individually discussed using the step-wise approach outlined. Agents deemed worthy to move forward were then re-examined and re-vetted through this work flow as new preclinical or trial data updates became available. CTEP, Cancer Therapy Evaluation Program; EWS, Ewing sarcoma; FDA, US Food and Drug Administration.

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References

1. Lawlor ER, Sorensen PH: Twenty Years on: What Do We Really Know about Ewing Sarcoma and What Is the Path Forward? Crit Rev Oncog. 2015;20(3–4):155–71. 10.1615/CritRevOncog.2015013553 - DOI - PMC - PubMed
1. Anderson ND, de Borja R, Young MD, et al. : Rearrangement bursts generate canonical gene fusions in bone and soft tissue tumors. Science. 2018;361(6405): pii: eaam8419. 10.1126/science.aam8419 - DOI - PMC - PubMed
2. F1000 Recommendation
1. Brohl AS, Patidar R, Turner CE, et al. : Frequent inactivating germline mutations in DNA repair genes in patients with Ewing sarcoma. Genet Med. 2017;19(8):955–8. 10.1038/gim.2016.206 - DOI - PMC - PubMed
2. F1000 Recommendation
1. Franzetti GA, Laud-Duval K, van der Ent W, et al. : Cell-to-cell heterogeneity of EWSR1-FLI1 activity determines proliferation/migration choices in Ewing sarcoma cells. Oncogene. 2017;36(25):3505–14. 10.1038/onc.2016.498 - DOI - PMC - PubMed
2. F1000 Recommendation
1. Pedersen EA, Menon R, Bailey KM, et al. : Activation of Wnt/β-Catenin in Ewing Sarcoma Cells Antagonizes EWS/ETS Function and Promotes Phenotypic Transition to More Metastatic Cell States. Cancer Res. 2016;76(17):5040–53. 10.1158/0008-5472.CAN-15-3422 - DOI - PMC - PubMed

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[1] Lawlor ER, Sorensen PH: Twenty Years on: What Do We Really Know about Ewing Sarcoma and What Is the Path Forward? Crit Rev Oncog. 2015;20(3–4):155–71. 10.1615/CritRevOncog.2015013553 - DOI - PMC - PubMed

[2] Lawlor ER, Sorensen PH: Twenty Years on: What Do We Really Know about Ewing Sarcoma and What Is the Path Forward? Crit Rev Oncog. 2015;20(3–4):155–71. 10.1615/CritRevOncog.2015013553 - DOI - PMC - PubMed

[3] Anderson ND, de Borja R, Young MD, et al. : Rearrangement bursts generate canonical gene fusions in bone and soft tissue tumors. Science. 2018;361(6405): pii: eaam8419. 10.1126/science.aam8419 - DOI - PMC - PubMed

F1000 Recommendation

[4] Anderson ND, de Borja R, Young MD, et al. : Rearrangement bursts generate canonical gene fusions in bone and soft tissue tumors. Science. 2018;361(6405): pii: eaam8419. 10.1126/science.aam8419 - DOI - PMC - PubMed

[5] F1000 Recommendation

[6] Brohl AS, Patidar R, Turner CE, et al. : Frequent inactivating germline mutations in DNA repair genes in patients with Ewing sarcoma. Genet Med. 2017;19(8):955–8. 10.1038/gim.2016.206 - DOI - PMC - PubMed

F1000 Recommendation

[7] Brohl AS, Patidar R, Turner CE, et al. : Frequent inactivating germline mutations in DNA repair genes in patients with Ewing sarcoma. Genet Med. 2017;19(8):955–8. 10.1038/gim.2016.206 - DOI - PMC - PubMed

[8] F1000 Recommendation

[9] Franzetti GA, Laud-Duval K, van der Ent W, et al. : Cell-to-cell heterogeneity of EWSR1-FLI1 activity determines proliferation/migration choices in Ewing sarcoma cells. Oncogene. 2017;36(25):3505–14. 10.1038/onc.2016.498 - DOI - PMC - PubMed

F1000 Recommendation

[10] Franzetti GA, Laud-Duval K, van der Ent W, et al. : Cell-to-cell heterogeneity of EWSR1-FLI1 activity determines proliferation/migration choices in Ewing sarcoma cells. Oncogene. 2017;36(25):3505–14. 10.1038/onc.2016.498 - DOI - PMC - PubMed

[11] F1000 Recommendation

[12] Pedersen EA, Menon R, Bailey KM, et al. : Activation of Wnt/β-Catenin in Ewing Sarcoma Cells Antagonizes EWS/ETS Function and Promotes Phenotypic Transition to More Metastatic Cell States. Cancer Res. 2016;76(17):5040–53. 10.1158/0008-5472.CAN-15-3422 - DOI - PMC - PubMed

[13] Pedersen EA, Menon R, Bailey KM, et al. : Activation of Wnt/β-Catenin in Ewing Sarcoma Cells Antagonizes EWS/ETS Function and Promotes Phenotypic Transition to More Metastatic Cell States. Cancer Res. 2016;76(17):5040–53. 10.1158/0008-5472.CAN-15-3422 - DOI - PMC - PubMed

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Emerging novel agents for patients with advanced Ewing sarcoma: a report from the Children's Oncology Group (COG) New Agents for Ewing Sarcoma Task Force

Affiliations

Emerging novel agents for patients with advanced Ewing sarcoma: a report from the Children's Oncology Group (COG) New Agents for Ewing Sarcoma Task Force

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