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。事实证明， 基底膜中的大多数基质细胞是肿瘤相关巨噬细胞(TAMs)，它们有助于 肿瘤微环境的异质性，促进基底膜的进展。我们最近做了 明确了导致巨噬细胞募集和极化的分子途径。我们的预赛 有数据表明，GBM中PTEN突变/缺失通过增强 巨噬细胞通过LOX募集。此外，我们还将TBK1确定为关键字 调节巨噬细胞极化的信号节点。目标1：我们将阐明 LOX介导的巨噬细胞在GBM中的募集；目标2：我们将确定 TBK1介导的基底膜巨噬细胞极化；目标3：我们将进行靶向临床前试验 LOX和TBK1结合标准护理和免疫关卡阻断发展 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.