Role of Receptor for Advanced Glycation End Product (RAGE) Pathway in Brain Tumors

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PROJECT SUMMARY Malignant gliomas are aggressive tumors that often recur within the resection margin after treatment. In addition to the development of targeted therapies against neoplastic cells, treatments aimed at tumor stroma are being considered to enhance conventional therapies. Tumor-associated inflammatory cells, such as macrophages and neutrophils, comprise a significant component of the glioma stroma and actively participate in angiogenesis, invasion and metastasis. These myeloid-derived cells express pattern recognition receptors such as the receptor for advanced glycation endproducts (RAGE) that constantly monitor the tumor micro- environment (TME). Engagement of RAGE by its ligands results in activation of multiple downstream pathways that regulate cell proliferation, survival, differentiation, migration, phagocytosis and autophagy. During the previous funding cycle, we demonstrated that upregulation of a common glioma RAGE ligand, S100B, promoted macrophage recruitment and altered their conversion into tumor-promoting cells. Furthermore, we showed that genetic ablation of RAGE in TME prolonged survival of glioma-bearing mice by attenuating tumor- associated inflammation and angiogenesis. These studies also revealed significant variability in the expression of other RAGE ligands in animal glioma models. The objective of this competing renewal is to evaluate the role of the RAGE pathway on TME remodeling and tumor progression in gliomas. Our central hypothesis is that gliomas release RAGE ligands that contribute to the polarization of inflammatory cells, and promote tumor growth and invasion. To test this, we propose the following experiments. In Aim 1 we will measure RAGE ligands in human glioma tumor samples in order to determine their physiological concentrations in the TME. Aim 2 will characterize changes in tumor inflammation after inhibition of RAGE ligands. Finally in Aim 3, we will determine the effect of RAGE activation on glioma progression and optimize the antitumor activity of targeting the RAGE axis. These studies will provide the first insights into the effect of the RAGE pathway and surgical trauma on glioma recurrence. This critically needed understanding of the mechanism of immune evasion in gliomas will be valuable in optimizing antiglioma therapies.