Abstract 5449: Characterization of clinically relevant mechanism of resistance to angiogenic inhibitors in different growth patterns of human colorectal cancer liver metastases (CRCLM) by studying the angiopoietins-Tie2 mechanisms

Abstract

Abstract Colorectal carcinoma (CRC) remains the third leading cause of cancer death in the Western world. Over 50% of CRC patients develop liver metastases (LM) and 90% will die from metastatic disease. Angiogenic inhibitors AIs (bevacizumab, Bev) were introduced with chemotherapy as first-line therapy for CRCLMs. While some patients respond well to this therapeutic strategy, the outcomes have fallen short of expectations. Recently we have reported the outcomes of resected CRCLM patients who have received neoadjuvant chemotherapy with or without AIs stratified by histologic growth patterns (HGPs): Desmoplastic HGP (DHGP), Pushing HGP (PHGP) and Replacement HGP (RHGP). The majority of metastases were either DHGPs, which derive the majority of their blood supply via sprouting angiogenesi,s or RHGP, which derive their blood supply from vessel co-option. When the neoadjuvant regimen included Bev, the DHGP patients more than doubled their 5-year overall survival (OS) compared to RHGP patients receiving the same Bev regimen. This OS difference was lost when both groups of patients were treated with chemo alone (no Bev). Although sprouting angiogenesis has been studied extensively and there is some understating of those mechanisms, we have no understanding of the mechanism behind co-option, and furthermore, apart from cytotoxic chemotherapy we have no targeted therapies for these patients. Theoretical Model: Cancer cells that arrive to the liver have to vascularize in order to increase in size, or as evidence has recently suggested, can grow avascularly in vascularized tissue by co-option of existing mature vessels. We hypothesize that there are several steps required for this process to occur. In our recent work, we have shown that cancer cell motility is essential for co-option. The angiopoietins-Tie2 mechanisms are critically involved in angiogenesis. Using human samples (chemonaïve, chemo-only and chemo plus Bev), we have evidence that Ang1-Tie2 mechanism is differently expressed in RHGP vs. DHGP metastases. The ratio of Ang2: Ang1 expression in DHGP tumors was higher compared to RHGP tumors, whereas VEGF appears to be equally expressed in both. Furthermore, a significant expression of Ang1 was detected in the hepatocytes at the interface region of the tumor and liver in RHGP. Thus, vascular quiescence maintained by Ang1-Tie2 mechanism prevails in RHGP verses DHGP metastasis; therefore this mechanism may be important in the development of vessel co-option vs. angiogenesis. Interestingly, Tie2 expression was expressed not only by vessels and tumor cells but also found in the leucocytes that were more abundant in DHGP vs. RHGP. This study will allow us to characterize the factors and mechanisms by which vessel co-option occurs in a metastatic setting and will stratify patients in terms of treatment. Citation Format: Nisreen Samir Ibrahim, Anthoula Lazaris, Stephanie Petrillo, Abdellatif Amri, Zu-Hua Gao, Peter Metrakos. Characterization of clinically relevant mechanism of resistance to angiogenic inhibitors in different growth patterns of human colorectal cancer liver metastases (CRCLM) by studying the angiopoietins-Tie2 mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5449.