Abstract 4810: Identification of molecular markers of pathological vascular subtypes with differential sensitivity to therapies targeting the VEGF pathway

Abstract

Abstract Therapeutic targeting of the VEGF pathway has not matched the efficacy suggested by preclinical tumor models. To date, the limitations of this form of therapy stem either from inherent or acquired resistance of the tumor vasculature to the reduction of VEGF signaling. Previous studies have described morphological phenotypes of different blood vessel types in human and mouse tumors. Recapitulation of these vascular phenotypes with a surrogate Ad-VEGFA164 model has shown differential sensitivity of these vascular subclasses to inhibitors of the VEGF pathway. The goal of the current study was to identify molecular markers for the various subtypes of pathological vessels and to assess whether similar molecular signatures are found in blood vessels in mouse tumor models and human disease. Using the Ad-VEGF-A164 flank model, microarray analysis was performed to identify molecular markers at each time-point, representing distinct stages of vessel development and maturation. We identified unique gene signatures at the various time-points and confirmed differential expression of the genes by qRT-PCR and/or immunohistochemistry. We found that vascular markers such as CD31, Ang2, and Tie1 were pan-endothelial markers at all time-points. However, other markers such as CD34, MECA-32, vWF, SMA, Tie2, CD105, and AQP1 were expressed on subclasses of endothelial cells. Expression of the molecular markers in tumors models revealed different subclasses of tumor vessels in patient-derived xenografts which were sensitive or resistant to anti-VEGF-A or anti-VEGFR-2 treatment. These vascular subtypes were also found in tissues from human breast and gastric cancers. Together these results indicate that multiple molecular markers can be used to identify unique pathological subclasses of tumor vessels. Some of these vascular subtypes may be insensitive to inhibitors targeting the VEGF pathways and their signatures may be useful biomarkers to predict vascular sensitivity to anti-angiogenic therapy. Citation Format: Beverly L. Falcon, Marguerita O'Mahony, Julie Stewart, Jiangang Liu, Janice A. Nagy, Qi Xue, Yong Pan, Cynthia Jeffries, Emma Hatten, Tim R. Holzer, Harold F. Dvorak, Aejaz Nasir, Bronek Pytowski, Laura Benjamin, Mark T. Uhlik. Identification of molecular markers of pathological vascular subtypes with differential sensitivity to therapies targeting the VEGF pathway. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4810. doi:10.1158/1538-7445.AM2014-4810