Sex-based Differences in Glioma

项目摘要 胶质母细胞瘤（GBM）是最常见的原发性恶性脑肿瘤， 积极的治疗流行病学数据表明， 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，最近 报告显示患有GBM的女性经历更长的存活。部分原因是缺乏机械性 尽管对这些结果背后的理解不同，但大多数研究都没有考虑到性别差异， 实验研究，不被认为是在治疗GBM，并不容纳在 临床试验设计为了填补这一知识空白，我们提出了这个计划项目赠款（P01）与长期- 描述GBM中基于性别的可操作差异的长期目标。该P01整合了 分子和细胞水平，以确定和利用性别特异性的分子机制， 男性GBM发生率增加，女性预后更好。这个多学科项目涉及 具有互补的专业知识和强大的合作历史的既定调查员。我们的出版 观察男性和女性在发病率和结局、遗传风险和致癌性方面的差异 现在已经结合了这些通路来构建P01，并使我们能够独特地揭示性别特异性机制 这为GBM患者的预后提供了信息，并为性别特异性治疗奠定了基础。我们将测试 中心假设，肿瘤细胞的性别差异（内在的）和肿瘤细胞的性别差异（内在的）的汇合， 微环境（外在）出现致癌事件（遗传）和正常的性 分化（表观遗传）是神经胶质瘤发生和疾病结果的机制差异的基础。 这一假设将通过三个协同项目加以解决，并得到三个赋能核心的支持。 由约书亚鲁宾博士领导的项目1将研究不同的男性和女性表观遗传机制， 影响转化和治疗反应。由詹姆斯康纳博士领导的项目2将审问 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的作用改变GBM生长的动力学。项目3，由Justin博士领导 Lathia将询问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的支持：㈠行政，㈡ 生物统计学/生物信息学协助，以及iii）由Jill博士领导的最先进的小鼠和人类GBM模型 Barnholtz-Sloan，Michael Berens，and Justin Lathia.这个P01是我们长期目标的一部分， 驱动GBM的特定机制，并可用于未来的治疗， 对所有GBM患者进行相同的治疗，以针对男性与女性的独特脆弱性进行治疗 GBM患者

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.