Conventional methods for evaluating tumor vasculature, such as microvessel density, do not capture critical 3-dimensional properties such as their spatial distribution, tortuosity, and distribution of different vessel sizes on a population basis. Such parameters are critical for understanding the biological effects of agents targeting tumor vasculature by different mechanisms. To address this critical unmet need, we developed a novel system platform which enables high-resolution 3-D, structural microvascular-pattern analysis and biomarker mining in support of preclinical and translational oncology discovery space. The OncoVasculomics™ platform captures, reconstructs, and then automatically and quantitatively analyzes microvascular structures and patterns indicative of response to targeted drug therapy.

Methods: The effect of two different anti-angiogenic therapeutic agents, bevacizumab and sunitinib, were assessed using OncoVasculomicsTM platform in Colo205 human colorectal cancer xenograft model. Animals bearing ∼200 mm3 sized tumors were treated for 7 days either with the appropriate vehicle, bevacizumab at 5 mg/kg (i.p. daily) or sunitinib at 30 mg/kg (p.o. daily). Mice were then systemically perfused with Mercox, the tissue was macerated and the resulting vascular tumor cast was imaged using a microCT. 3-dimensional tumor vascular tree was derived using proprietary segmentation and reconstruction software. OncoVasculomicsTM vascular mining software was then used to derive various vascular morphology parameters.

Results: Mean tumor sizes did not significantly differ between the Bevacizumab, sutent or vehicle treatment groups at the end of the experiment. Whole tumor 3D micro vessel density (MVD) was similar between the treatment groups: vehicle (bevacizumab) 2.7+/-0.6 % of total tumor volume, bevacizumab 2.2+/-0.4%, vehicle (sunitinib) 2.9+/-0.3% and sunitinib 2.5+/-0.3%. Bevacizumab and sunitinib treatments resulted in 20% and 16% decrease in total tumor MVD, respectively. Bevacizumab treatment resulted in 8.2 % “cold spot” or low vascular density region generation. In contrast, sunitinib was ∼5-fold more efficient in generating “cold spots” at a rate of 37% (sunitinib vs. vehicle tumors). Bevacizumab's anti-vascular activity targeted vessels of 28 um in diameter and larger. However, the majority of sunitinib's activity had effect on vessels 21-35 um in diameter.

This study demonstrates that a comprehensive 3d OncoVasculomic™ analysis may provide important mechanistic and efficacy insights into the vascular effects of different classes of drugs targeting tumor vasculature.

Citation Format: Raul A. Brauner, Kongbin Kang, Yanchun Wu, George N. Naumov, John V. Heymach. Onco Vasculomics(tm): A 3-d tumor vasculature assessment methodology for quantifying mechanism and efficacy of discovery-stage anti-cancer compounds. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4421. doi:10.1158/1538-7445.AM2013-4421