Project 2: Molecular and Clinical Inputs Affecting Optimization of Glioma Therapy

项目2：影响神经胶质瘤优化治疗的分子和临床输入 项目摘要/摘要： 胶质母细胞瘤(GBM)是最恶性和最常见的原发脑肿瘤，分为 几个分子亚基分别为PN-GBM、MES-GBM和CL-GBM。因为单元格的子集 这些肿瘤具有干细胞样特性，对DNA损伤剂相对不敏感，如辐射(XRT)、 因此对治疗具有高度抵抗力。在PN-GBM中，干细胞与血管相邻， 在血管周围龛(PVN)。在其他GBM亚型中，干细胞样细胞分布于肿瘤各处。 为了找到更好的GBM疗法，我们需要提高我们对干细胞生物学的理解--以及 非干细胞样基底膜细胞作为分子亚型的功能。我们之前已经证明了 这两种细胞类型的动态相互转换在治疗后几小时内发生，并且可以成功地 数学建模，为优化辐射计划以最大限度地提高小鼠存活率提供基础 PN-GBM模型。然而，其他GBM亚型的最佳辐射给药计划是 未知。此外，护理标准要求给予替莫唑胺(TMZ)佐剂。 与辐射同时发生。根据我们的初步数据，我们假设(1)一个数学模型 MES-GBM的辐射和TMZ响应将不同于PN-GBM。(2)建立了MES-GBM的辐射和TMZ响应的数学模型 MES-GBM的辐射和TMZ响应与PN-GBM不同。(3)存在 GBM的特征，如果改变，将从根本上增强所有GBM的响应，而不管 子类型。我们提出了三个具体目标来检验这些假设：目标1：提高我们对 PN-GBM中的PVN，并利用这一认识优化TMZ/XRT的联合治疗。目标2：创建 MES-GBM中干细胞分布更均匀的辐射响应数学模型。目标 3.确定将提高所有GBM的护理标准的战略，而不分亚型。我们的目标是 将我们的发现转化为未来的临床试验。

Project 2: Molecular and clinical inputs affecting optimization of glioma therapy Project Summary / Abstract: Glioblastomas (GBM) are the most malignant and common of the primary brain tumors and are divided into several molecular subgroups denoted PN-GBM, MES-GBM and CL-GBM. Because of a subset of cells with stem-like properties, these tumors are relatively insensitive to DNA damaging agents, such as radiation (XRT), and are consequently highly resistant to therapy. In PN-GBM the stem-like cells live adjacent to blood vessels, in the perivascular niche (PVN). In other GBM subtypes, stem-like cells are distributed throughout the tumors. In order to identify better GBM therapies, we need to improve our understanding of the biology of stem- and non-stem-like GBM cells as a function of molecular subtype. We have previously demonstrated that the dynamic inter-conversion of these two cell types occurs within hours of therapy and can be successfully mathematically modeled, providing a basis for optimizing radiation schedules to maximize survival in mouse models of PN-GBM. However, optimum radiation administration schedules for other GBM subtypes are unknown. Additionally, standard of care calls for the administration of adjuvant temozolomide (TMZ) concurrently with radiation. Based on our preliminary data, we hypothesize that (1) a mathematical model of radiation and TMZ response in MES-GBM will be different than that for PN-GBM, (2) a mathematical model of radiation and TMZ response in MES-GBM will be different than that for PN-GBM, (3) there are biological characteristics of GBM that, if altered, would fundamentally enhance the responses of all GBMs regardless of subtype. We propose three specific aims to test these hypotheses: Aim 1: Improve our understanding of the PVN in PN-GBM and use this understanding to optimize combined TMZ/XRT therapy. Aim 2: Create a mathematical model of radiation response in MES-GBM where the stem cells are more evenly distributed. Aim 3. Identify strategies that would improve the standard of care for all GBM regardless of subtype. Our goal is to translate our findings into future clinical trials.