| Target Validation Information | |||||
|---|---|---|---|---|---|
| Target ID | T21960 | ||||
| Target Name | Angiopoietin-2 | ||||
| Target Type | Clinical Trial |
||||
| Action against Disease Model | AMG 386 | A VEGF-driven rat corneal angiogenesis model was used to establish a direct non-t uMorigenic anti-neovascular effect of AMG 386, with Ang2 expression in the nascent vasculature demonstrated by in situ hybridization. Exposure to AMG 386 led to dose-dependent inhibition of VEGF-mediated corneal angiogenesis. Reversible epiphyseal plate thickening was observed in rats treated with high doses of AMG 386 (75 and 200 mg/kg twice weekly for 2 weeks), a characteristic pharmacological sequela of anti-angiogenic therapy in growing rats that is not expected to occur in adults in whom endochondrial bone formation has ceased. AMG 386 was shown to neutralize Ang2-Tie2 and Ang1-Tie2 interactions with IC50 values of 23 and 900 pM, respectively. In nude mice bearing subcutaneous Colo205 h uMan colorectal t uMor xenografts, exposure to AMG 386 inhibited t uMor growth when administered either 3 or 28 days following t uMor cell injection at an optimal dose of 0.6 mg/kg twice weekly. | [553088] | Drug Info | |
| The Effect of Target Knockout, Knockdown or Genetic Variations | Current models suggest that binding of angiopoietin-2 (Ang-2) to its endothelial Tie2 receptor prevents receptor phosphorylation, destabilizes blood vessels, and promotes vascular permeability. In contrast, binding of angiopoietin-1 (Ang-1) induces Tie2 receptor activation and supports the formation of mature blood vessels covered by pericytes. Despite the intense research to decipher the role of angiopoietins during physiological neovascularization and t uMour angiogenesis, a mechanistic understanding of angiopoietin function on vascular integrity and remodelling is still incomplete. We therefore assessed the vascular morphology of two mouse mammary carcinoma xenotransplants (M6378 and M6363) which differ in their natural angiopoietin expression. M6378 displayed Ang-1 in t uMour cells but no Ang-2 in t uMour endothelial cells in vivo. In contrast, M6363 t uMours expressed Ang-2 in the t uMour vasculature, whereas no Ang-1 expression was present in t uMour cells.We stably transfected M6378 mouse mammary carcinoma cells with h uMan Ang-1 or Ang-2 and investigated the consequences on the host vasculature, including ultrastructural morphology. Interestingly, M6378/Ang-2 and M6363 t uMours displayed a similar vascular morphology, with intrat uMoural haemorrhage and non-functional and abnormal blood vessels. Pericyte loss was prominent in these t uMours and was accompanied by increased endothelial cell apoptosis. Thus, overexpression of Ang-2 converted the vascular phenotype of M6378 t uMours into a phenotype similar to M6363 t uMours. Our results supportthe hypothesis that Ang-1/Tie2 signalling is essential for vessel stabilization and endothelial cell/pericyte interaction, and suggest that Ang-2 is able to induce a switch of vascular phenotypes within t uMours | [553088] | |||
| References | |||||
| Ref 553088 | AMG 386: profile of a novel angiopoietin antagonist in patients with ovarian cancer. Expert Opin Investig Drugs. 2011 Feb;20(2):297-304. doi: 10.1517/13543784.2011.549125. Epub 2011 Jan 6. | ||||
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