Abstract A8: LY2228820 dimesylate, a p38-MAPK inhibitor, modulates angiogenic endothelial cord formation in vitro and in vivo.

Abstract

Abstract LY2228820 dimesylate is a highly selective small molecule inhibitor of p38-mitogen-activated protein kinase (p38-MAPK) that is currently under clinical investigation for human malignancies. p38-MAPK is implicated in a wide range of biological processes, in particular those processes that support tumorigenesis. One such process, angiogenesis, is required for tumor growth and metastasis, and many new cancer therapies are therefore directed against the tumor vasculature. p38-MAPK is activated in endothelial cells upon growth factor stimulation and is involved in the secretion of growth factors and cytokines, but the role this activation plays in angiogenesis is not well defined. Using an in vitro co-culture endothelial cord formation assay (a surrogate of angiogenesis), we investigated the role of p38-MAPK in growth factor and tumor-driven angiogenesis by pharmacological inhibition of p38-MAPK using LY2228820 dimesylate and by shRNA gene knockdown. Inhibition of p38-MAPK by LY2228820 dimesylate led to a significant decrease in growth factor (VEGF, FGF, EGF) and IL-6 induced endothelial cord formation and an even more dramatic decrease in tumor-driven cord formation from a variety of tumor cell lines representing a range of histologies. Inhibition of p38-MAPK in tumor cells led to decreased cytokine secretion of VEGF, EGF, IL-6, IL-8, and other proangiogenic factors. Small molecule inhibitor results were substantiated by similar results obtained using p38-MAPK specific shRNA. Consequently, it appears that p38-MAPK plays a role in endothelial cell angiogenesis and tumor cell cytokine secretion. LY2228820 dimesylate effects on an in vivo angiogenesis Matrigel plug assay revealed a significant decrease in hemoglobin content (a measure of functional neoangiogenesis) which correlated with decreased pericyte coverage of the vessels. These results implicate p38-MAPK in tumor angiogenesis, and suggest that in vivo inhibition of p38-MAPK may lead to increased vascular permeability and/or induction of vascular normalization. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A8.