Abstract 367: Identification of tumor cell-derived factors associated with resistance to anti-VEGF therapy in non-small cell lung cancer
Authors: Sullivan Laura A. , Carbon Juliet G. , Toombs Jason , Xie Yang , Minna John D. , Brekken Rolf A. 
Published: February 2011

Abstract
Vascular endothelial growth factor-A (VEGF) functions during physiological and pathological angiogenesis. Strategies that inhibit VEGF are now an established anti-cancer paradigm. We have developed a human monoclonal antibody (mAb), r84 that recognizes mouse and human VEGF and specifically blocks VEGF binding and activation of VEGFR2 but does not interfere with VEGF:VEGFR1 interaction. Therefore, r84 allows for the functional evaluation of tumor cell and stromal cell derived VEGF-induced activation of VEGFR2 signaling in tumor progression and provides a useful comparison to other anti-VEGF strategies in tumor xenograft models. Bevacizumab (bev) is a humanized mAb that binds human VEGF and prevents VEGF-induced activation of VEGFR1 and VEGFR2. The FDA has approved bev for the treatment of several tumor types, including non-squamous non-small cell lung cancer (NSCLC). Given the cost, toxicities and great variation in patient response to bev, it would be desirable to have biomarkers that predict response and allow for “personalized” treatment. The variation of NSCLC response to anti-VEGF therapy suggests a complex mechanism of drug action within tumors and indicates that some tumors may be intrinsically resistant to bev. Therefore, successful use of anti-VEGF therapy may rely on a better understanding of genes associated with responsiveness or resistance. To evaluate intrinsic resistance to anti-VEGF therapy we have performed an in vivo screen of a panel of NSCLC xenografts (n=11) for response to anti-VEGF therapy (bev or r84). We identified NSCLC xenografts that are very sensitive, moderately sensitive or display intrinsic resistance to bev or r84 therapy with final tumor weight treatment/control (T/C) ratios ranging from 0.1 to 0.65. Sensitive tumors had low T/C ratios and relevant vascular changes including decreased tumor microvessel density, lymphatic vessel density, and VEGFR2 expression. Microarray analysis of sensitive and resistant cell lines have been used to generate a preliminary gene signature that may mark relevant tumor cell derived genes associated with response to anti-VEGF treatment. Validation of this signature is currently underway. We conclude that NSCLC xenografts can exhibit dramatically different response phenotypes to anti-VEGF mAbs. A better understanding of the mechanisms of response to anti-VEGF therapy may lead to the development of more effective therapies and could ultimately assist in the identification of patients that would benefit the most from anti-VEGF strategies.
Supported by the Randall Bridwell Lung Cancer Research Grant from Uniting Against Lung Cancer and Lung Cancer SPORE P50CA70907.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 367.