Abstract 1741: Inhibition of pcsk9 impairs the development of vessel co-option and potentiates anti-angiogenic therapy in colorectal cancer liver metastases

Abstract

Abstract Colorectal cancer liver metastatic (CRCLM) tumours present as two main histopathological growth patterns (HGPs) including desmoplastic HGP (DHGP) and replacement HGP (RHGP). The DHGP tumours obtain their blood supply by sprouting angiogenesis, whereas the RHGP tumours utilize an alternative vascularisation known as vessel co-option. In vessel co-option, the cancer cells hijack the mature sinusoidal vessels to obtain blood supply. Vessel co-option has been reported as an acquired mechanism of resistance to anti-angiogenic treatment in CRCLM. Herein, we show the connection between serum cholesterol concentration and vessel co-option development in CRCLM. Our clinical data suggested that the elevation of serum cholesterol levels correlates with the risk of developing vessel co-opting tumours. Moreover, inhibition of PCSK9, the key modulator of cholesterol metabolism, significantly attenuated the development of vessel co-opting CRCLM tumours and sensitized the tumours to anti-angiogenic therapy in vivo. Altogether, these data suggest the importance of cholesterol in the development of vessel co-option tumours and propose that inhibiting PCSK9 is a promising strategy to overcome resistance to anti-angiogenic therapy in CRCLM. Citation Format: Miran Rada, Lucyna Krzywon, Audrey Kapelanski-Lamoureux, Stephanie Petrillo, Andrew Reynolds, Anthoula Lazaris, Nabil Seidah, Peter Metrakos. Inhibition of pcsk9 impairs the development of vessel co-option and potentiates anti-angiogenic therapy in colorectal cancer liver metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1741.