| Target Validation Information | |||||
|---|---|---|---|---|---|
| Target ID | T44141 | ||||
| Target Name | Angiopoietin-1 | ||||
| Target Type | Clinical Trial |
||||
| Drug Potency against Target | AMG 386 | Drug Info | Ki = 0.9 nM | [552468] | |
| Action against Disease Model | AMG 386 | AMG 386 is an investigational recombinant peptide-Fc fusion protein (???eptibody??? containing a peptide sequence that binds Ang1 and Ang2. AMG 386 reduces t uMor angiogenesis by selectively neutralizing Ang1 and Ang2, thereby blocking their interaction with the Tie2 receptor. In a t uMor xenograft mouse model, systemic treatment with AMG 386 inhibited t uMor growth, with subsequent disappearance of all measurable t uMors in some of the animals and evidence of an antiangiogenic mechanism of action | [553052] | Drug Info | |
| The Effect of Target Knockout, Knockdown or Genetic Variations | We investigated the participation of AT1 receptor-signaling in cancer progression using murine Lewis lung carcinoma (LLC) cells, which express AT1 receptor, and AT1a receptor gene-deficient (AT1a-/-) mice. When LLC cells were implanted subcutaneously into wild-type (WT) mice, developed t uMors showed intensive angiogenesis with an induction of vascular endothelial growth factor (VEGF) a. Compared with WT mice, t uMor growth and t uMor-associated angiogenesis was reduced in AT1a-/- mice with reduced expression of VEGFa. In AT1a-/- mice, administration of the AT1 receptor antagonist, TCV-116, showed further reductions of t uMor growth, t uMor-associated angiogenesis, and VEGFa expression. In vitro study, the expression of VEGFa mRNA and the production of VEGFa protein in LLC cells were significantly increased by AII, which were cancelled by AT1 receptor antagonist, CV-11974. Although the expression of other angiogenic factors, such as angiopoietin-1, angiopoietin-2, epidermal growth factor, and VEGF receptor 2 mRNA, was also investigated in t uMor tissues, the expression of VEGFa was most correlated with t uMor size among those other angiogenic factors. VEGFa induction by AT1 receptor-signaling in both host and t uMor tissues is one of key regulators of t uMor growth and t uMor-associated angiogenesis. In conclusion, t uMor tissue RAS as well as host tissueRAS were found to have an important role in t uMor growth | [553052] | |||
| References | |||||
| Ref 553052 | Phase 1 study of AMG 386, a selective angiopoietin 1/2-neutralizing peptibody, in combination with chemotherapy in adults with advanced solid tumors. Clin Cancer Res. 2010 Jun 1;16(11):3044-56. doi: 10.1158/1078-0432.CCR-09-3368. Epub 2010 May 25. | ||||
| Ref 552468 | Suppression of angiogenesis and tumor growth by selective inhibition of angiopoietin-2. Cancer Cell. 2004 Nov;6(5):507-16. | ||||
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