Development of a phenotypic profiling platform with high predictive value for the identification of novel antiangiogenic drugs

Monday, October 24, 2011 — Poster Session I
Noon – 2:00 p.m.	Natcher Conference Center	NCI	CANCER-1

Authors

• M Aparicio
• P Amornphimoltham
• R Weigert
• J Lewis
• F Cuttitta
• E Zudaire

Abstract

Deregulation of angiogenesis plays a major role in a cancer. Existing FDA approved drugs target single proangiogenic moieties and have shown promising yet limited efficacy in the clinic. Here we introduce a novel high-content fluorescence platform for discovery of antiangiogenic agents. It features a primary screening based on high-content growth and tube formation assays using phenotypically-defined fluorescent endothelial cells. The effect of drugs on growth was assessed using fluorescence as a reporter quantifiable signal. Tube formation assays were performed in matrigel and quantitatively evaluated in an automated fashion with the newly developed image analysis software AngioApplication. 2000 small molecules were screened; 46 were growth inhibitors, 70 significantly blocked tube formation and 11 showed both activities. Seven lead compounds were tested in an in vivo xenograft model of angiogenesis and two were as effective as bevacizumab. The angiogenesis gene expression profile of endothelial cells recovered from drug-exposed tube formation assays was predictive of tumor growth inhibition in vivo. Chicken chorioallantoic assays and xenograft intravital microscopy and immunocytochemistry revealed the antiangiogenic mechanism of action of the tested small molecules. In summary, we have developed a screening platform which shows high predictive value and has allowed the discovery of novel antiangiogenic drugs.

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