Sex-based Differences in Glioma

神经胶质瘤的性别差异

基本信息

批准号：
10463728
负责人：
Justin D. Lathia
金额：
$ 201.97万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-14 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10463728
关键词：
Address Behavior Bioinformatics Biometry Cell Cycle Cell Cycle Regulation Cells Clinical Trials Design Development Disease Outcome Epigenetic Process Event Experimental Models Female Foundations Four Core Genotypes Future Genetic Genetic Risk Genomics Genotoxic Stress Glioblastoma Glioma Gliomagenesis Goals Growth Human Immune Incidence Integrins Iron Knockout Mice Knowledge LCN2 gene Malignant Neoplasms Malignant neoplasm of brain Mediator of activation protein Metabolism Microglia Modeling Modification Molecular Mus Oncogenic Organ Outcome Pathway interactions Patients Phenotype Physiology Ploidies Positioning Attribute Prognosis Program Research Project Grants Publishing Recording of previous events Reporting Research Personnel Sex Differences Sex Differentiation Signal Transduction Survivors Testing Translational Research Tumor Suppressor Proteins Woman aggressive therapy anticancer research base chemotherapy driver mutation epidemiologic data experience experimental study immune activation individualized medicine innovation iron metabolism junctional adhesion molecule macrophage male multidisciplinary neoplastic cell novel strategies patient prognosis response sex sexual dimorphism translational medicine treatment response tumor tumor growth tumor microenvironment tumor progression tumor-immune system interactions tumorigenic

项目摘要

PROJECT SUMMARY Glioblastoma (GBM), the most common primary malignant brain tumor, remains uniformly lethal despite aggressive therapies. Epidemiological data demonstrate an increased incidence of cancer in males across many tumors including GBM, genomic analyses have identified sex-specific molecular alterations, and recent reports demonstrate that women with GBM experience longer survival. Due in part to a lack mechanistic understanding behind these outcomes, differences between sexes are not accounted for in the majority of experimental studies, are not considered in the treatment of GBM, and are not accommodated in clinical trial design. To fill this knowledge gap, we propose this Program Project Grant (P01) with the long- term goal of delineating actionable sex-based differences in GBM. This P01 integrates analyses at the molecular and cellular levels to identify and exploit sex-specific molecular mechanisms that underlie the increased incidence of GBM for males and better prognosis for females. This multi-disciplinary project involves established investigators with complementary expertise and a strong collaborative history. Our published observations of differences between males and females in incidence and outcome, genetic risk, and oncogenic pathways have now coalesced to build this P01 and uniquely position us to reveal sex-specific mechanisms that inform GBM patient prognosis and serve as the foundation for sex-specific therapies. We will test the central hypothesis that the confluence of sex differences in tumor cells (intrinsic) and the microenvironment (extrinsic) emerging from oncogenic events (genetic) and normal sexual differentiation (epigenetic) underlies mechanistic differences in gliomagenesis and disease outcome. This hypothesis will be addressed via three synergistic projects and supported by three enabling cores. Project 1, led by Dr. Joshua Rubin, will interrogate distinct male and female epigenetic mechanisms that impact transformation and treatment response. Project 2, led by Dr. James Connor, will interrogate the mechanisms by which sex-specific microenvironmental interactions, including differences in iron metabolism (tumor and host), microglia, and macrophages, alter the dynamics of GBM growth. Project 3, led by Dr. Justin Lathia, will interrogate sex-specific mechanisms of microglia activation and their impact on GBM growth. These projects will be supported by three integrated cores offering: i) administrative, ii) biostatistical/bioinformatics assistance, and iii) state-of-the-art mouse and human GBM models led by Drs. Jill Barnholtz-Sloan, Michael Berens, and Justin Lathia. This P01 is part of our long-term goal to identify sex- specific mechanisms that drive GBM and can be leveraged for future therapies that move beyond using the same treatments for all GBM patients to tailoring treatments to the unique vulnerabilities of male versus female patients with GBM.

项目概要胶质母细胞瘤（GBM）是最常见的原发性恶性脑肿瘤，尽管积极的治疗。流行病学数据表明，男性癌症发病率有所增加包括 GBM 在内的许多肿瘤，基因组分析已经确定了性别特异性分子改变，并且最近报告表明，患有 GBM 的女性的生存期更长。部分原因是缺乏机制对这些结果背后的理解，性别之间的差异在大多数情况下都没有得到考虑实验研究，不考虑 GBM 的治疗，也不适应临床试验设计。为了填补这一知识空白，我们提出了这项计划项目拨款（P01）与长期描述 GBM 中基于性别的可操作差异的长期目标。此 P01 集成了以下分析：分子和细胞水平来识别和利用性别特异性分子机制男性 GBM 发病率增加，女性预后更好。这个多学科项目涉及建立了具有互补专业知识和强大合作历史的研究人员。我们发表的观察男性和女性在发病率和结果、遗传风险和致癌方面的差异现在，这些途径已经联合起来构建了这个 P01，并使我们能够独特地揭示性别特异性机制为 GBM 患者的预后提供信息，并作为性别特异性治疗的基础。我们将测试中心假设是肿瘤细胞性别差异（内在的）和致癌事件（遗传）和正常性行为产生的微环境（外在）分化（表观遗传）是神经胶质瘤发生和疾病结果机制差异的基础。这一假设将通过三个协同项目得到解决，并得到三个支持核心的支持。项目 1 由 Joshua Rubin 博士领导，将探讨不同的男性和女性表观遗传机制，影响转化和治疗反应。项目 2 由 James Connor 博士领导，将询问性别特异性微环境相互作用的机制，包括铁代谢的差异（肿瘤和宿主）、小胶质细胞和巨噬细胞改变 GBM 生长的动态。项目 3，由 Justin 博士领导 Lathia 将探讨小胶质细胞激活的性别特异性机制及其对 GBM 生长的影响。这些项目将得到三个综合核心产品的支持：i) 管理，ii) 生物统计/生物信息学协助，以及 iii) 由 Dr. 领导的最先进的小鼠和人类 GBM 模型。吉尔巴恩霍尔茨-斯隆、迈克尔·贝伦斯和贾斯汀·拉西亚。这个 P01 是我们识别性别的长期目标的一部分- 驱动 GBM 的特定机制，可用于未来的治疗，超越使用对所有 GBM 患者采用相同的治疗方法，根据男性与女性的独特脆弱性定制治疗方法 GBM 患者。