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， 弥漫性桥脑胶质瘤(DIPG)是一种高度致命性的亚型。DIPG通常表现出突变 组蛋白H3，即H3K27M，可导致神经胶质瘤的发生。然而，细胞信令事件 促进DIPG增长还没有完全了解。我们已经发现并最近表明DIPG是依赖的 细胞外信号调节蛋白5(ERK5)对细胞增殖和生存的影响。然而，几个关键的 DIPG对ERK5功能的认识空白仍然存在。我们将使用创新的同基因DIPG模型 与DIPG的成熟模式相结合，以解决本提案中的几个问题。具体来说， 我们假设ERK5通过胶质瘤的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)。意义：支持我们的初步数据 并验证我们的假设，我们将研究ERK5在三个目标中的作用。目的1：揭示ERK5在脑内的功能 GAMS和DIPG细胞旁分泌信号的重要性将潜在地提供有价值的知识 适用于开发新的治疗方式。目标2：通过以下方式建立新的范式 了解靶向多条ERK通路的动态特征。目标3：ERK5包含两个 反式激活结构域和激活域不同于所有其他ERK。在这里，我们将描述 这些结构域及其对胶质瘤生长的贡献。冲击力。该项目利用体内和体内独一无二的 研究高侵袭性脑瘤的体外模型系统。我们的研究将揭示分子机制 和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和 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.