E-Poster Presentation 34th Lorne Cancer Conference 2022

Eribulin normalises tumour vasculature by inducing mural cell maturation (#309)

Bo He 1 , Zhijie Li 1 , Kira Wood 1 , Bruce A Littlefield 2 , Ruth Ganss 1
  1. Harry Perkins Institute of Medical Research, The University of Western Australia Medical School, Nedlands, WA, Australia
  2. Translational Medicine, Global Oncology, Eisai Inc., Cambridge, MA, USA

Tumour blood vessels are abnormal and limit T cell access and function, thus protecting the tumour from immune attacks. Strategies to alleviate these vascular abnormalities, in a process known as ‘normalisation’, enhance lymphocyte infiltration and anti-tumour immunity. Tumour vascular normalisation can be achieved by targeting endothelial cells or mural cells, so-called pericytes. Eribulin is a tubulin binding drug approved for treatment of metastatic breast cancer. Besides inhibiting mitotic spindle formation in cancer cells, eribulin also exerts non-mitotic effects by modulating the tumour microenvironment including the tumour vasculature. How this is effected remains unknown. Here, we established an in vitro model of angiogenic pericytes which displays highly proliferative or synthetic properties such as production of extracellular matrix. At low dose, eribulin treatment reduces pericyte proliferation coincident with increased contractile marker expression, an effect which is not observed with other clinically approved tubulin binding drugs such as paclitaxel or vinorelbine. In vivo, in a highly angiogenic pancreatic tumour model, pericytes surrounding the tumour vasculature display a synthetic phenotype. Intravenous eribulin treatment selectively induces pericytes to change from an immature synthetic phenotype to a more mature contractile state consistent with our in vitro observations. This effect is not induced in tumours treated with paclitaxel or vinorelbine. “Forced” pericyte maturation under eribulin treatment in vivo affects the whole angiogenic vasculature as demonstrated by enhanced VE-cadherin expression in endothelial cells and improved endothelial cell/pericyte alignment. Importantly, eribulin-induced blood vessel normalisation improves overall tumour perfusion and mitigates hypoxia. The capacity of low dose eribulin treatment to enhance T cell infiltration and immunotherapy needs to be further investigated in combination therapies. This work was funded by Eisai Inc.