Developing Novel Therapeutic Approaches Targeting Macrophages in GBM

项目摘要 GBM仍然是最致命的脑癌，没有有效的治疗方法。已经显示 GBM中的大多数基质细胞是肿瘤相关巨噬细胞（TAM）， 肿瘤微环境异质性，促进GBM进展。我们最近 定义了导致巨噬细胞募集和极化的分子途径。我们的初步 数据显示，GBM中的PTEN突变/缺失通过增强免疫应答而触发免疫应答。 通过LOX募集巨噬细胞。此外，我们还确定TBK 1是一个关键因素， 调节巨噬细胞极化的信号传导节点。目的1：我们将阐明 LOX介导的巨噬细胞在GBM中的募集;目的2：我们将确定LOX介导的巨噬细胞募集的分子基础。 TBK 1介导GBM中的巨噬细胞极化;目标3：我们将进行临床前试验， LOX和TBK 1联合标准治疗和免疫检查点阻断， GBM患者的新治疗方法。

Project Summary GBM remains the most lethal brain cancer with no effective therapeutics. It has been shown that the majority of stromal cells in GBM are tumor-associated macrophages (TAMs), which contribute to tumor microenvironment heterogeneity and promote GBM progression. We have recently defined molecular pathways leading to macrophage recruitment and polarization. Our preliminary data showed that PTEN mutation/deletion in GBM triggers immune response by enhancing macrophage recruitment through LOX. In addition, we have also identified TBK1 as a key signaling node regulating macrophage polarization. Aim 1: we will elucidate the mechanism of LOX mediated macrophage recruitment in GBM; Aim 2: we will determine the molecular basis of TBK1 mediated macrophage polarization in GBM; Aim 3: we will perform preclinical trials targeting LOX and TBK1 in combination with standard of care and immune checkpoint blockade to develop novel therapeutic approach for GBM patients.