Endosialin is expressed in high grade and advanced sarcomas: Evidence from clinical specimens and preclinical modeling

Rouleau, Cecile; Smale, Robert; Fu, Yao‐Shi; Hui, Guodong; Wang, Fei; Hutto, Elizabeth; Fogle, Robert; Jones, C. S.; Krumbholz, Roy; Roth, Stephanie; Curiel, Maritza; Ren, Yi; Wallar, Gina; Miller, Glenn A.; Schmid, Steven M.; Horten, Bruce; Teicher, Beverly A.

doi:10.3892/ijo.2011.1020

Cited by 22 publications

(21 citation statements)

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“…In most cases, perivascular staining was moderate to strong which is also in agreement with previous studies [19, 20]. Similar to the other tissue types examined, normal skeletal muscle demonstrated variable moderate staining of endothelial cells and strong perivascular cell staining, a finding that is consistent with those of Naylor, et al [29].…”

Section: Resultssupporting

confidence: 91%

“…Further examinations of gene expression patterns in normal and neoplastic tissue have found a consistent up-regulation of endosialin/TEM-1 expression in tumor neovessels. These include enhanced expression of endosialin/TEM-1 in stroma of human colorectal cancer [10, 15], breast cancer [16, 17], histiocytomas [18] and expression directly on tumor cells of mesenchymal origin including sarcoma [19, 20] and melanoma [21, 22]. Human endosialin/TEM-1 expression has also been reported in highly invasive glioblastoma, anaplastic astrocytomas and metastatic carcinomas [21, 23].…”

Section: Introductionmentioning

confidence: 99%

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Novel antibody probes for the characterization of endosialin/TEM-1

et al. 2016

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Endosialin (Tumor Endothelial Marker-1 (TEM-1), CD248) is primarily expressed on pericytes of tumor-associated microvasculature, tumor-associated stromal cells and directly on tumors of mesenchymal origin, including sarcoma and melanoma. While the function of endosialin/TEM-1 is incompletely understood, studies have suggested a role in supporting tumor growth and invasion thus making it an attractive therapeutic target. In an effort to further understand its role in cancer, we previously developed a humanized anti-endosialin/TEM-1 monoclonal antibody (mAb), called ontuxizumab (MORAb-004) for testing in preclinical and clinical studies. We herein report on the generation of an extensive panel of recombinant endosialin/TEM-1 protein extracellular domain (ECD) fragments and novel mAbs against ECD motifs. The domain-specific epitopes were mapped against ECD sub-domains to identify those that can detect distinct structural motifs and can be potentially formatted as probes suitable for diagnostic and functional studies. A number of mAbS were shown to cross-react with the murine and human protein, potentially allowing their use in human animal models and corresponding clinical trials. In addition, pairing of several mAbs supported their use in immunoassays that can detect soluble endosialin/TEM-1 (sEND) in the serum of healthy subjects and cancer patients.

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Section: Resultssupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Novel antibody probes for the characterization of endosialin/TEM-1

et al. 2016

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“…Endosialin is known to be expressed in the stromal compartment of virtually every human tumor (1, 2, 4–7). In addition to the stromal compartment expression, endosialin is expressed by tumor cells in a subset of tumors, primarily of mesenchymal origin.…”

Section: Discussionmentioning

confidence: 99%

“…In some tumors, endosialin is expressed on the surface of the cancer cells, in addition to its expression on tumor-associated pericytes (5). This is true for tumors of mesenchymal origin as well as some epithelial tumors with mesenchymal features (7). …”

Section: Introductionmentioning

confidence: 96%

A First-in-Human Phase I Study of MORAb-004, a Monoclonal Antibody to Endosialin in Patients with Advanced Solid Tumors

Díaz

Coughlin

Weil

et al. 2015

Clinical Cancer Research

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Purpose Endosialin (TEM-1, CD248) is a protein expressed on the surface of activated mesenchymal cells, including certain subsets of tumors. Preclinical models suppressing endosialin function have shown antitumor activity. A humanized monoclonal antibody, MORAb-004, was engineered to target endosialin and is the first agent in clinical development for this mesenchymal cell target. Experimental Design This first-in-human, open-label, phase I study recruited patients with treatment-refractory solid tumors. MORAb-004 was administered intravenously once weekly in 4-week cycles. Objectives included determination of the safety of multiple infusions of MORAb-004, identification of the maximum tolerated dose (MTD), pharmacokinetic modeling, detection of any anti-human antibody response, and assessment of objective radiographic response to therapy. Results Thirty-six patients were treated at 10 dose levels of MORAb-004, ranging from 0.0625 to 16 mg/kg. Drug-related adverse events were primarily grade 1–2 infusion toxicities. Dose-limiting toxicity of grade 3 vomiting was observed at 16 mg/kg. Eighteen of 32 evaluable patients across all doses achieved disease stability, with minor radiographic responses observed in 4 patients (pancreatic neuroendocrine, hepatocellular, and sarcoma tumor types). Pharmacokinetics showed MORAb-004 accumulation beginning at 4 mg/kg and saturable elimination beginning at 0.25 mg/kg. Exposure increased in a greater-than-dose-proportional manner with terminal half-life increasing proportionally with dose. The MTD was identified as 12 mg/kg. Conclusions Preliminary antitumor activity was observed. Safety profile, pharmacokinetics, and early antitumor activity suggest that MORAb-004 is safe at doses up to 12 mg/kg and should be studied further for efficacy.

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“…This research identified the TEM-1 gene product as the FB5 antigen [14]. Further examination of gene expression patterns in normal and neoplastic tissue have indicated up-regulation of TEM-1 expression in tumor neovessels within human colorectal cancer [10], breast cancer [15, 16], histiocytomas [17] as well as expression directly on tumor cells of mesenchymal origin including sarcoma [18,19] and melanoma [20]. Human TEM-1 expression has also been reported in highly invasive glioblastoma, anaplastic astrocytomas, and metastatic carcinomas [21].…”

Section: Introductionmentioning

confidence: 99%

Influence of tumor microenvironment on prognosis in colorectal cancer: Tissue architecture-dependent signature of endosialin (TEM-1) and associated proteins

et al. 2014

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Tumor survival is influenced by interactions between tumor cells and the stromal microenvironment. One example is Endosialin (Tumor Endothelial Marker-1 (TEM-1) or CD248), which is expressed primarily by cells of mesenchymal origin and some tumor cells. The expression, as a function of architectural masking, of TEM-1 and its pathway-associated proteins was quantified and examined for association with five-year disease-specific survival on a colorectal cancer (CRC) cohort divided into training (n=330) and validation (n=164) sets. Although stromal expression of TEM-1 had prognostic value, a more significant prognostic signature was obtained through linear combination of five compartment-specific expression scores (TEM-1 Stroma, TEM-1 Tumor Vessel, HIF2α Stromal Vessel, Collagen IV Tumor, and Fibronectin Stroma). This resulted in a single continuous risk score (TAPPS: TEM-1 Associated Pathway Prognostic Signature) which was significantly associated with decreased survival on both the training set [HR=1.76 (95%CI: 1.44-2.15); p<0.001] and validation set [HR=1.38 (95%CI: 1.02-1.88); p=0.04]. Importantly, since prognosis is a critical clinical question in Stage II patients, the TAPPS score also significantly predicted survival in the Stage II patient (n=126) cohort [HR=1.75 (95%CI: 1.22-2.52); p=0.002] suggesting the potential of using the TAPPS score to assess overall risk in CRC patients, and specifically in Stage II patients.

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Endosialin is expressed in high grade and advanced sarcomas: Evidence from clinical specimens and preclinical modeling

Cited by 22 publications

References 1 publication

Novel antibody probes for the characterization of endosialin/TEM-1

Novel antibody probes for the characterization of endosialin/TEM-1

A First-in-Human Phase I Study of MORAb-004, a Monoclonal Antibody to Endosialin in Patients with Advanced Solid Tumors

Influence of tumor microenvironment on prognosis in colorectal cancer: Tissue architecture-dependent signature of endosialin (TEM-1) and associated proteins

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