Abstract 1477: LRG1 blockade normalizes tumor vasculature and improves efficacy of chemotherapy

Abstract

Abstract In cancer blood vessels are dysfunctional, poorly perfused and leaky. Malfunctioning vessels contribute to the pro-oncogenic environment and limit the efficacy of current systemically administered drugs. Normalizing the tumor vasculature to improve vessel permeability, reduce hypoxia and vascular leakage and enhance drug delivery, has become an experimental objective in cancer research. This study was carried out to investigate the effect of blocking the secreted glycoprotein leucine-rich alpha-2-glycoprotein 1 (LRG1) on tumor vascular function, and evaluate the impact it has on the efficacy of the common standard of care chemotherapeutic drug cisplatin. Under normal conditions LRG1 is mainly expressed in the liver but also in other tissues such as bone marrow and immune cells. LRG1 has been described in multiple reports to be a serum prognostic biomarker in several cancers, for example lung, prostate, colorectal and breast. LRG1 promotes dysfunctional vessel growth by disrupting TGFβ signaling. We demonstrate that in Lrg1-/- mice and following treatment with a LRG1 function-blocking antibody (15C4) tumor growth was inhibited. In addition, we show using RNAscope that following subcutaneous grafting of the B16F0 and LL2 tumor cell lines in mice, Lrg1 is induced in tumor endothelial cells. Despite having no effect on total vessel area, the density was decreased upon LRG1 blockade, with the persisting larger vessels exhibiting improved vessel structure as evidenced by increased pericyte and basement membrane endothelial cell coverage. Better mural cell association with tumor vascular endothelial cells and basement membrane coverage are also indicators of vessel stabilization and maturation. Using a systemically delivered fluorescent lectin tracer to mark perfused vessels, we observed a significant increase in tumor perfusion in mice treated with 15C4. Lastly, vessel normalization, through LRG1 antibody blockade, significantly enhanced the efficacy of cisplatin chemotherapy as shown by a slower tumor growth rate and increased tumor cell death compared to monotherapy. These data further corroborate the hypothesis that inhibition of LRG1 improves the delivery, and hence efficacy, of a cytotoxic drug. In conclusion, deletion or inhibition of LRG1 results in an improved vascular configuration and function, and the efficacy of chemotherapy. LRG1 blockade may therefore represent a novel strategy to enhance vessel health and improve the efficacy of cancer therapeutics. Citation Format: Camilla Pilotti, Marie N O'Connor, David Kallenberg, Laura Dowsett, Jestin George, Stephen E. Moss, John Greenwood. LRG1 blockade normalizes tumor vasculature and improves efficacy of chemotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1477.