Abstract
Abstract
Angiogenesis is an essential key process in tumor growth, invasion, and metastasis. Several angiogenesis inhibitors have been clinically proven to treat a wide variety of cancer types. These agents target either the vascular endothelial growth factor (VEGF) or the intracellular tyrosine kinase domain of VEGF receptors. Despite the encouraging clinical benefits, there are multiple challenges such as significant toxic effects and rapid development of drug resistance which limit the long-term benefits of VEGF-targeted therapy. Emerging evidence suggests that tumors can bypass VEGF/VEGFR inhibition by up-regulating other pro-angiogenic pathways to compensate for VEGF inhibition. For these reasons, additional strategies to inhibit tumor vasculature are being sought. In this regard, F16, a new compound developed by Rumbaugh-Goodwin Institute for Cancer Research, harbors the potential for suppressing VEGF-driven angiogenesis by selectively blocking the extracellular domain of VEGFR2, which plays a crucial role in endothelial cell proliferation, survival, and migration. F16 has shown a remarkable efficacy in inhibiting VEGFR-associated tyrosine kinase activities. On the other hand, Tie-2 receptor is predominantly expressed in the endothelium and has been shown to facilitate VEGF-mediated angiogenesis. Therefore, we hypothesize that dual targeting of VEGFR2 and Tie-2 using F16 and T2i respectively will result in augmented angiogenesis inhibition. To test our hypothesis, human umbilical vein endothelial cells (HUVECs) were used as a model for our initial validation studies. Our preliminary data indicated that combining F16 and T2i significantly inhibited HUVECs proliferation compared to monotherapies (P<0.001) and 90% inhibition of HUVECs proliferation was observed at 1μM of the drug combination. Moreover, the ability of the indicated drugs to inhibit angiogenesis was further evaluated using a Matrigel-based tube formation assay. Using the scoring system developed by our laboratory, combining F16 and T2i at 1μM scored five pluses, indicating that individual cells were well-separated as compared to monotherapies (three pluses and two pluses respectively). These findings clearly indicated that concurrent blockade of VEGFR2 and Tie-2 represented a new strategy to potentiate angiogenesis inhibition. However, further studies are required to test whether there would be imposing changes in the growth rates of human cancers implanted in a mouse model, and whether these changes are attributed to changes in tumor vasculatures. These studies will ultimately lead us to understand the pharmacodynamics of F16 and Tie-2 inhibitor for better clinical applications in the future. (This research was supported by Royal Dames of Cancer Research Inc., Ft. Lauderdale, Florida.)
Citation Format: Khalid Alhazzani, Thanigaivelan Kanagasabai, Saad Alobid, Appu Rathinavelu. The impact of dual targeting VEGFR2 and Tie-2 on angiogenesis using in vitro model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3257.