Endosialin expression in soft tissue sarcoma as a potential marker of undifferentiated mesenchymal cells

Thway, Khin; Robertson, David; Jones, Robin L.; Selfe, Joanna; Shipley, Janet; Fisher, Cyril; Isacke, Clare M.

doi:10.1038/bjc.2016.214

Cited by 25 publications

(25 citation statements)

References 21 publications

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“…Consequently, endosialin was considered a potential therapeutic target in sarcomas. Other studies confirmed these findings …”

Section: Introductionsupporting

confidence: 70%

“…Other studies confirmed these findings. 6 Cancer July 15, 2019 Ontuxizumab is a humanized immunoglobulin G1κ antibody directed against endosialin and the first of this class to undergo clinical evaluation. Nonclinical pharmacological studies have shown that ontuxizumab has the ability to interfere with specific endosialin receptorligand interactions.…”

Section: Introductionmentioning

confidence: 99%

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A phase 1 and randomized controlled phase 2 trial of the safety and efficacy of the combination of gemcitabine and docetaxel with ontuxizumab (MORAb‐004) in metastatic soft‐tissue sarcomas

Jones

Chawla

Schöffski

et al. 2019

Cancer

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Background Ontuxizumab, a humanized monoclonal antibody, targets endosialin (tumor endothelial marker 1 [TEM‐1] or CD248), which is expressed on sarcoma cells and is believed to be involved in tumor angiogenesis. This is the first trial to evaluate ontuxizumab in patients with sarcoma. Methods Part 1 was an open‐label, dose‐finding, safety lead‐in: 4, 6, or 8 mg/kg with gemcitabine and docetaxel (G/D; 900 mg/m 2 gemcitabine on days 1 and 8 and 75 mg/m 2 docetaxel on day 8). In part 2, patients were randomized in a double‐blind fashion in 2:1 ratio to ontuxizumab (8 mg/kg) or a placebo with G/D. Randomization was stratified by 4 histological cohorts. Results In part 2 with 209 patients, no significant difference in progression‐free survival between ontuxizumab plus G/D (4.3 months; 95% confidence interval [CI], 2.7‐6.3 months) and the placebo plus G/D (5.6 months; 95% CI, 2.6‐8.3 months) was observed ( P = .67; hazard ratio [HR], 1.07; 95% CI, 0.77‐1.49). Similarly, there was no significant difference in median overall survival between the 2 groups: 18.3 months for the ontuxizumab plus G/D group (95% CI, 16.2‐21.1 months) and 21.1 months for the placebo plus G/D group (95% CI, 14.2 months to not reached; P = .32; HR, 1.23; 95% CI, 0.82‐1.82). No significant differences between the treatment groups occurred for any efficacy parameter by sarcoma cohort. The combination of ontuxizumab plus G/D was generally well tolerated. Conclusions Ontuxizumab plus G/D showed no enhanced activity over chemotherapy alone in soft‐tissue sarcomas, whereas the safety profile of the combination was consistent with G/D alone.

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“…Consequently, endosialin was considered a potential therapeutic target in sarcomas. Other studies confirmed these findings …”

Section: Introductionsupporting

confidence: 70%

Section: Introductionmentioning

confidence: 99%

A phase 1 and randomized controlled phase 2 trial of the safety and efficacy of the combination of gemcitabine and docetaxel with ontuxizumab (MORAb‐004) in metastatic soft‐tissue sarcomas

Jones

Chawla

Schöffski

et al. 2019

Cancer

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“…In addition, it has been shown that the presence of endosialin is essential for the cellular growth and the migration of pericytes, which are key regulators of tumor neoangiogenesis [18,19]. Interestingly, in some tumors, namely sarcoma and neuroblastoma, the expression of endosialin/TEM1 is not only limited to the tumor stroma and neovasculature but it is also present on tumor cell surface [11,[20][21][22].…”

Section: Introductionmentioning

confidence: 99%

Preclinical Evaluation and Dosimetry of [111In]CHX-DTPA-scFv78-Fc Targeting Endosialin/Tumor Endothelial Marker 1 (TEM1)

et al. 2020

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Purpose: Endosialin/tumor endothelial marker-1 (TEM1) is an attractive theranostic target expressed by the microenvironment of a wide range of tumors, as well as by sarcoma and neuroblastoma cells. We report on the radiolabeling and preclinical evaluation of the scFv78-Fc, a fully human TEM1-targeting antibody fragment cross-reactive with mouse TEM1. Procedures: The scFv78-Fc was conjugated with the chelator p-SCN-Bn-CHX-A"-DTPA, followed by labeling with indium-111. The number of chelators per molecule was estimated by mass spectrometry. A conventional saturation assay, extrapolated to infinite antigen concentration, was used to determine the immunoreactive fraction of the radioimmunoconjugate. The radiopharmaceutical biodistribution was assessed in immunodeficient mice grafted with Ewing's sarcoma RD-ES and neuroblastoma SK-N-AS human TEM1-positive tumors. The full biodistribution studies were preceded by a dose-escalation experiment based on the simultaneous administration of the radiopharmaceutical with increasing amounts of unlabeled scFv78-Fc. Radiation dosimetry extrapolations to human adults were obtained from mouse biodistribution data according to established methodologies and additional assumptions concerning the impact of the tumor antigenic sink in the cross-species translation. Results: [ 111 In]CHX-DTPA-scFv78-Fc was obtained with a radiochemical purity 9 98 % after 1 h incubation at 42°C and ultrafiltration. It showed good stability in human serum and 9 70 % immunoreactive fraction. Biodistribution data acquired in tumor-bearing mice confirmed fast blood clearance and specific tumor targeting in both xenograft models. The radiopharmaceutical off-target uptake was predominantly abdominal. After a theoretical injection of [ 111 In]CHX-DTPA-scFv78-Fc to the reference person, the organs receiving the highest absorbed dose would be the spleen (0.876 mGy/MBq), the liver (0.570 mGy/MBq) and the kidneys (0.298 mGy/MBq). The Electronic supplementary material The online version of this article (

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“…The B6FS cell line originates from a poorly differentiated fibrosarcoma ( 40 ). In poorly differentiated tumors, cancer cells are characterized by scant phenotypic similarity with cells of origin, mild pleomorphism, as well as intense mitotic activity ( 55 , 56 ). It is noteworthy that fibrosarcoma is a particularly heterogeneous tumor type, taking into account morphology, differentiation and behavior ( 57 ).…”

Section: Discussionmentioning

confidence: 99%

Heparin regulates B6FS cell motility through a FAK/actin cytoskeleton axis

et al. 2016

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Soft tissue sarcomas are rare, heterogeneous tumors of mesenchymal origin with an aggressive behavior. Heparin is a mixture of heavily sulfated, linear glycosaminoglycan (GAG) chains, which participate in the regulation of various cell biological functions. Heparin is considered to have significant anticancer capabilities, although the mechanisms involved have not been fully defined. In the present study, the effects of unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) on B6FS fibrosarcoma cell motility were examined. Both preparations of heparin were shown to both enhance B6FS cell adhesion (p<0.01 and p<0.05), and migration (p<0.05), the maximal effect being evident at the concentration of 10 µg/ml. The utilization of FAK-deficient cells demonstrated that the participation of FAK was obligatory for heparin-dependent fibrosarcoma cell adhesion (p<0.05). The results of confocal microscopy indicated that heparin was taken up by the B6FS cells, and that UFH and LMWH induced F-actin polymerization. Heparitinase digestion demonstrated that the endogenous heparan sulfate (HS) chains did not affect the motility of the B6FS cells (p>0.05, not significant). In conclusion, both UFH and LMWH, through a FAK/actin cytoskeleton axis, promoted the adhesion and migration of B6FS fibrosarcoma cells. Thus, our findings indicate that the responsiveness of fibrosarcoma cells to the exogenous heparin/HS content of the cancer microenvironment may play a role in their ability to become mobile and metastasize.

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Endosialin expression in soft tissue sarcoma as a potential marker of undifferentiated mesenchymal cells

Cited by 25 publications

References 21 publications

A phase 1 and randomized controlled phase 2 trial of the safety and efficacy of the combination of gemcitabine and docetaxel with ontuxizumab (MORAb‐004) in metastatic soft‐tissue sarcomas

A phase 1 and randomized controlled phase 2 trial of the safety and efficacy of the combination of gemcitabine and docetaxel with ontuxizumab (MORAb‐004) in metastatic soft‐tissue sarcomas

Preclinical Evaluation and Dosimetry of [111In]CHX-DTPA-scFv78-Fc Targeting Endosialin/Tumor Endothelial Marker 1 (TEM1)

Heparin regulates B6FS cell motility through a FAK/actin cytoskeleton axis

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