The purpose of this study is to: (1) examine whether vessel co-option is associated with a lack of response to anti-angiogenic therapy in advanced colorectal cancer patients, (2) identify whether inhibition of pathways associated with vessel co-option sensitizes to anti-angiogenic therapy in vivo.
Sprouting angiogenesis is the process whereby new blood vessels are induced to sprout from existing vessels. The growth of metastatic tumors is considered to require sprouting angiogenesis. This hypothesis has driven the development and clinical application of vascular endothelial growth factor (VEGF) targeted agents, such as bevacizumab. However, responses to such agents in cancer patients, including metastatic colorectal cancer (CRC), are variable. It is not currently clear why this is the case and we have no way of selecting patients suitable for such therapies.
Importantly, it is now evident that tumors can also utilize a number of putative ‘VEGF-independent’ angiogenesis mechanisms, the existence of which may limit the efficacy of VEGF-targeted therapy. One such mechanism is ‘vessel co-option,’ whereby tumors engulf existing local blood vessels as they invade into surrounding host tissue. Published studies have reported that this mechanism occurs in ∼28-30% of CRC liver metastases.
Here we present data from a retrospective study of patients with CRC liver metatases that were treated with bevacizumab. We demonstrate that, in this patient cohort, the presence of vessel co-option in liver metastases was strongly associated with lack of response to bevacizumab. We also show that a similar result is observed in a mouse model of colorectal cancer liver metastasis. Interestingly, when we disable actin nucleation activity in colorectal cancer cells, vessel co-option is compromised and sensitivity to VEGF-targeted therapy is restored in vivo. These data demonstrate a potential role for vessel co-option as a negative predictive biomarker for anti-angiogenic therapy and also have consequences for the development of novel therapies for targeting tumor angiogenesis.
Citation Format: Sophia Frentzas, Victoria L. Thompson, Peter B. Vermeulen, Shane Foo, Gina Brown, David Cunningham, Andrew R. Reynolds. Vessel co-option in colorectal cancer liver metastases mediates resistance to VEGF-targeted therapy. [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 2997. doi:10.1158/1538-7445.AM2014-2997