Cabozantinib in patients with advanced Ewing sarcoma or osteosarcoma (CABONE): a multicentre, single-arm, phase 2 trial

Italiano, Antoîne; Mir, Olivier; Mathoulin‐Pélissier, Simone; Penel, Nicolas; Piperno‐Neumann, Sophie; Bompas, Emmanuelle; Chevreau, Christine; Duffaud, Florence; Entz‐Werlé, Natacha; Saâda, Esma; Ray‐Coquard, Isabelle; Lervat, Cyril; Gaspar, Nathalie; Marec‐Bérard, Perrine; Pacquement, Hélène; Wright, John J.; Toulmonde, Maud; Bessede, Alban; Crombé, Amandine; Kind, Michèle; Bellera, C.; Blay, Jean‐Yves

doi:10.1016/s1470-2045(19)30825-3

Cited by 226 publications

(225 citation statements)

References 33 publications

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“…If the first clinical trial including the anti-VEGF antibody bevacizumab was disappointing [127], encouraging results emerged from initial clinical trials using the MKI sorafenib, which targets intracellular kinase activity of VEGFRs [125,126]. Since then, several MKIs like regorafenib [158,159], pazopanib [160,161], and more recently cabozantinib, have been reported to have beneficial effects in advanced OS and Ewing sarcoma bone tumors [162]. Accordingly, these agents had promising therapeutic results in selected patients, probably through the combined action on both angiogenic vascular compartment and OS cells in which they inhibit multiple growth factor pathways with potential oncogenic activity (c-MET, c-KIT).…”

Section: Discussionmentioning

confidence: 99%

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The Osteosarcoma Microenvironment: A Complex but Targetable Ecosystem

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Crenn

et al. 2020

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Osteosarcomas are the most frequent primary bone sarcomas, affecting mainly children, adolescents, and young adults, and with a second peak of incidence in elderly individuals. The current therapeutic management, a combined regimen of poly-chemotherapy and surgery, still remains largely insufficient, as patient survival has not improved in recent decades. Osteosarcomas are very heterogeneous tumors, both at the intra- and inter-tumor level, with no identified driver mutation. Consequently, efforts to improve treatments using targeted therapies have faced this lack of specific osteosarcoma targets. Nevertheless, these tumors are inextricably linked to their local microenvironment, composed of bone, stromal, vascular and immune cells and the osteosarcoma microenvironment is now considered to be essential and supportive for growth and dissemination. This review describes the different actors of the osteosarcoma microenvironment and gives an overview of the past, current, and future strategies of therapy targeting this complex ecosystem, with a focus on the role of extracellular vesicles and on the emergence of multi-kinase inhibitors.

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Section: Discussionmentioning

confidence: 99%

“…Preclinical and in vitro data reinforced the relevance of MKI in OS. One phase II multi-centric clinical trial has just been published, exploring cabozantinib in advanced relapsed OS and Ewing sarcoma [162]. Encouraging responses were reported for both pathologies.…”

Section: The Multi-kinase Inhibitors (Mkis) As Promising Therapies Inmentioning

confidence: 99%

The Osteosarcoma Microenvironment: A Complex but Targetable Ecosystem

Corre

Verrecchia

Crenn

et al. 2020

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“…In osteosarcoma, preclinical studies have shown that cabozantinib is able to inhibit proliferation and migration of osteosarcoma cells through the ERK and AKT signaling pathways ( 50 ). The French sarcoma group had carried out a multicenter, phase II trial involving patients with advanced or metastatic osteosarcoma after failure of other systemic therapy ( 20 ). Ninety osteosarcoma patients received cabozantinib orally every day continuous 28-days cycles until unacceptable toxicity or disease progression was observed.…”

Section: Tkis Reported In Registered Clinicaltrials For Osteosarcoma mentioning

confidence: 99%

Receptor Tyrosine Kinases in Osteosarcoma Treatment: Which Is the Key Target?

2020

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Recent clinical trials have shown several multi-target tyrosine kinase inhibitors (TKIs) to be effective in the treatment of osteosarcoma. However, these TKIs have a number of targets, and it is yet unclear which of these targets has a key role in osteosarcoma treatment. In this review, we first summarize the TKIs that were studied in clinical trials registered on ClinicalTrials.gov. Further, we compare and discuss the targets of these TKIs. We found that TKIs with promising therapeutic effect for osteosarcoma include apatinib, cabozantinib, lenvatinib, regorafenib, and sorafenib. The key targets for osteosarcoma treatment may include VEGFRs and RET. The receptor tyrosine kinases (RTKs) MET, IGF-1R, AXL, PDGFRs, KIT, and FGFRs might be relevant but unimportant targets for osteosarcoma treatment. Inhibition of one type of RTK for the treatment of osteosarcoma is not effective. It is necessary to inhibit several relevant RTKs simultaneously to achieve a breakthrough in osteosarcoma treatment. This review provides comprehensive information on TKI targets relevant in osteosarcoma treatment, and it will be useful for further research in this field.

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“…The clinical manifestations of the disease still vary from person to person. Although efforts have been made to improve treatment options and outcomes, patients in the diagnosis of metastatic or recurrent disease remain a dire prognosis [9]. The most commonly used initial chemotherapy strategies are three, depending in part on institutional preferences and patient age.…”

Section: Identifcation Of Hub Genes In the Salmon Module And Darkoranmentioning

confidence: 99%

The Oxidative Stress Pathway May be an Important Pathway Leading to The Recurrence of Ewing Sarcoma —— Based On Weighted Gene Co-Expression Network Analysis

Song

et al. 2020

Preprint

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Background The role of gene and pathway in recurrence of Ewing sarcoma (ES) was not clear. Thus, we investigated the biological role and underlying mechanism of gene and pathway in recurrence of ES.Methods Data sets of patients with ES were collected from the GEO database. We used dataset GSE63155 and GSE63156 to construct co-expression networks by weighted gene co-expression network analysis (WGCNA). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed by Database for Annotation, Visualization and Integrated Discovery (DAVID). ResultsWe can find that genes with significant interactions in the genes of the recurrence group include SRSF11, TRIM39, SOCS3,NUPL2,COPS5. They work primarily through the oxidative stress pathway.Conclusion Through our research, for the first time found that ES by SRSF11 TRIM39, SOCS3, NUPL2, COPS5 interaction, activation of phosphorylation of bone and oxidative stress is affecting tumor recurrence. 4.SelvanathanSP, Graham GT, Grego AR, Baker TM, Hogg JR, Simpson M, Batish M, Crompton B, Stegmaier K, Tomazou EM et al: EWS-FLI1 modulated alternative splicing of ARID1A reveals novel oncogenic function through the BAF complex. Nucleic acids research 2019, 47(18):9619-9636. 5. Zhang B, Horvath S: A general framework for weighted gene co-expression network analysis. Statistical applications in genetics and molecular biology 2005, 4:Article17. 6. The Gene Ontology (GO) project in 2006. Nucleic acids research 2006, 34(Database issue):D322-326. 7. Dwight SS, Eppig JT et al: Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nature genetics 2000, 25(1):25-29.8.

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Cabozantinib in patients with advanced Ewing sarcoma or osteosarcoma (CABONE): a multicentre, single-arm, phase 2 trial

Cited by 226 publications

References 33 publications

The Osteosarcoma Microenvironment: A Complex but Targetable Ecosystem

The Osteosarcoma Microenvironment: A Complex but Targetable Ecosystem

Receptor Tyrosine Kinases in Osteosarcoma Treatment: Which Is the Key Target?

The Oxidative Stress Pathway May be an Important Pathway Leading to The Recurrence of Ewing Sarcoma —— Based On Weighted Gene Co-Expression Network Analysis

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