Abstract 17: Inhibition of LRG1 normalizes tumor vessels and improves efficacy of cancer therapeutics
Authors: Greenwood John , O'Connor Marie N. , Kallenberg David , Jackstadt Rene-Filip , Watson Angharad , Ohme Julia , Dowsett Laura , George Jestin , Wang Xiaomeng , Ager Ann , Sansom Owen J. , Moss Stephen E. 
Published: August 2018

Introduction: The aim of this study was to determine whether deletion of the gene coding for the secreted glycoprotein, leucine-rich alpha-2-glycoprotein 1 (LRG1), or blockade of its action through function-blocking antibody treatment, improves tumor vascular function.

Experimental Procedures: The role of LRG1 was investigated in subcutaneous B16/F0 and LL2 mouse tumor models and in genetically engineered mouse models of intestinal (ApcMin) and pancreatic (KPC) cancers. Tumors were evaluated in wild type (WT) or Lrg1-/- mice or in WT mice treated with 15C4, a LRG1 blocking antibody. Tumor growth and survival were monitored and post-mortem analysis of vascular density, structure and function were undertaken. The effect of blocking LRG1 function on the efficacy of cisplatin or adoptive T cell therapy in B16/F0 tumor-bearing mice was determined.

Results: In Lrg1-/- mice or following functional blockade of LRG1 in WT animals there was a significant reduction in B16/F0 and LL2 tumor growth and improved survival in the ApcMin and KPC tumor-bearing mice. Vascular density was reduced in the B16/F0 and the KPC tumors but not in those of ApcMin. Most notably, we found that loss of LRG1 results in improved pericyte-endothelial cell association in the B16/F0 and ApcMin tumors. In the B16/F0 tumors we also observed an increase in the proportion of perfused vessels, and a reduction in vessel permeability and tumour hypoxia, consistent with our hypothesis that LRG1 is a vascular disrupting factor. Normalizing tumor vasculature to enhance vessel patency, reduce hypoxia and vascular leakage, and improve delivery of therapeutics has become a major objective. We therefore evaluated the effect of inhibiting LRG1 activity with the 15C4 antibody on the efficacy of cisplatin or adoptive CD8+ T cell therapy on B16/F0 tumor growth. Co-therapy revealed a highly significant reduction in tumor growth compared with monotherapy alone.

Conclusions: These data show that LRG1 subverts physiological angiogenesis by promoting dysfunctional vessel growth, and that therapeutic targeting of LRG1 reduces tumor neovascular growth and normalizes vascular function. We propose, therefore, that LRG1 is a potential therapeutic target in cancer, and that its inhibition may aid the delivery and efficacy of tumour therapeutics.

Funded by grants from the Medical Research Council UK, The Wellcome Trust, Rosetrees Trust, UCL Business and Moorfields Eye Hospital Special Trustees.

Citation Format: John Greenwood, Marie N. O'Connor, David Kallenberg, Rene-Filip Jackstadt, Angharad Watson, Julia Ohme, Laura Dowsett, Jestin George, Xiaomeng Wang, Ann Ager, Owen J. Sansom, Stephen E. Moss. Inhibition of LRG1 normalizes tumor vessels and improves efficacy of cancer therapeutics [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 17.