Targeting extracellular signaling-regulated kinase 5 (ERK5) in brain tumors and their microenvironment

背景：高级别胶质瘤是儿童癌症相关死亡的主要原因之一， 弥漫性脑内桥胶质瘤（DIPG）是一种高致死性亚型。DIPG通常表现出突变， 组蛋白H3，称为H3K27M，其导致胶质瘤的发生。然而，细胞信号事件， 促进DIPG生长还没有完全了解。我们已经发现并最近表明，DIPG依赖于 细胞外信号调节激酶5（ERK 5）的增殖和生存。然而，一些关键 DIPG中ERK 5功能的知识缺口仍然存在。我们将使用创新的同基因DIPG模型， 结合成熟的DIPG模型，解决本提案中的几个问题。具体地说， 我们假设ERK 5通过胶质瘤内在效应和促胶质瘤活性促进生长， 选择胶质瘤相关的小胶质细胞和巨噬细胞（GAM）。重要性：支持我们的初步数据 为了验证我们的假设，我们将研究ERK 5在三个目标中的作用。目的1：揭示ERK5的功能， GAM和DIPG细胞旁分泌信号的重要性将提供有价值的知识， 适用于开发新的治疗模式。目标2：建立新的范式， 了解靶向多个ERK通路的动态特征。目的3：ERK5包含两个 与所有其他ERK不同的是，它具有转录激活结构域和激酶结构域。在这里，我们将描述的功能作用， 这些结构域及其对胶质瘤生长的贡献。冲击该项目利用了独特的体内和体内 体外模型系统来研究高度侵袭性的脑肿瘤。我们的研究将为分子机制 ERK5在脑肿瘤中的翻译相关性，并广泛适用于其他类型的癌症， 神经科学

Background: High-grade gliomas are among the leading cause of cancer-related death in children, with diffuse intrinsic pontine glioma (DIPG) being a highly lethal subtype. DIPG commonly exhibits a mutation in histone H3, referred to as H3K27M, which leads to gliomagenesis. However, the cell signaling events that promote DIPG growth are not fully understood. We have discovered and recently shown that DIPGs are reliant on extracellular signal-regulated kinase 5 (ERK5) for proliferation and survival. However, several critical knowledge gaps of ERK5 function in DIPG remain. We will use an innovative syngeneic DIPG model in combination with well-established models of DIPG to address several questions in this proposal. Specifically, we hypothesize that ERK5 promotes growth through both glioma intrinsic effects and pro-glioma activities of select glioma associated microglia and macrophages (GAMs). Significance: To support our preliminary data and test our hypothesis we will study the role of ERK5 in three aims. Aim 1: Revealing functions of ERK5 in GAMs and the importance of paracrine signaling with DIPG cells will provide valuable knowledge potentially applicable to the development of new therapeutic modalities. Aim 2: Building a new paradigm by understanding the dynamic characteristics of targeting multiple ERK pathways. Aim 3: ERK5 contains both a transactivation domain and kinase domain unlike all other ERKs. Here we will delineate the functional role of these domains and their contribution to glioma growth. Impact. This project leverages unique in vivo and in vitro model systems to study a highly aggressive brain tumor. Our research will inform molecular mechanisms and translational relevance of ERK5 in brain tumors, and be broadly applicable to other types of cancer and neurosciences.