Sex-based Differences in Glioma

项目总结 胶质母细胞瘤(GBM)是最常见的原发恶性脑肿瘤，尽管如此，其致命性仍然是一致的 积极的治疗方法。流行病学数据显示，全世界男性的癌症发病率都在上升 包括基底膜在内的许多肿瘤，基因组分析已经确定了性别特异性的分子改变，最近 报告表明，患有GBM的女性存活时间更长。部分原因是缺乏机械性 了解这些结果背后的原因，性别之间的差异在大多数情况下都没有得到解释 实验研究，在治疗基底膜时不考虑，也不包括 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赠款(P01)与长期- 描述GBM中基于性别的可操作差异的学期目标。本P01综合分析了 分子和细胞水平，以识别和利用性别特异的分子机制，这些分子机制是 男性GBM发病率增加，女性预后较好。这一多学科的项目涉及 成熟的调查人员具有互补的专业知识和强大的合作历史。我们出版的 男性和女性在发病率和转归、遗传风险和致癌方面的差异观察 现在，各种途径已经结合在一起，构建了这一P01，并使我们处于独特的位置，以揭示性别特有的机制 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 中心假设肿瘤细胞中的性别差异(固有的)和 致癌事件(遗传)和正常性行为产生的微环境(外在) 分化(表观遗传学)是胶质瘤发生和疾病转归的机制差异的基础。 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。 由约书亚·鲁宾博士领导的项目1将询问不同的男性和女性表观遗传机制 冲击转化和处理反应。项目2，由詹姆斯·康纳博士领导，将审问 性别特有的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，改变了基底膜生长的动力学。项目3，由贾斯汀博士领导 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。 这些项目将由三个综合核心提供支持：一)行政，二) 生物统计学/生物信息学援助，以及iii)由Jill博士领导的最先进的小鼠和人类GBM模型 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，并可用于未来的治疗，而不是使用 对所有GBM患者进行相同的治疗，以针对男性和女性的独特脆弱性进行量身定制的治疗 肾小球基底膜病患者。

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.