Molecular basis for the impact of sex on brain tumorigenesis

摘要 在接下来的一年里，大约22,000名美国人将患上胶质母细胞瘤(GBM)，几乎相同数量的人 都会因此而死。此外，我们可以可靠地预测，在22,000例新病例中，8,500例将发生在女性，而 其余13,500例将发生在男性。此外，虽然明年女性GBM患者的中位存活率 预计将在17到22个月之间，而男性将接近16个月。的分子碱基 这些在发病率和存活率方面一贯而显著的性别差异是无法解释的。在缺少 解释，不可能完全知道性别差异对在 实验室和临床上用于治疗基底膜。确定潜在的性别差异的目标机制 生存是这个项目的重点，我们的目标是改善所有GBM患者的预后。建立在我们的 在此RO1的前一个资助期内支持的已发表和初步研究，我们现在假设 细胞衰老的性别差异是胶质母细胞瘤(GBM)性别差异的原因 发病率和存活率。由于放化疗引起的衰老是阻止肿瘤的一种机制 生长，我们将专注于赋予女性细胞更强的衰老能力的机制 比男性同龄人对DNA损伤的反应更好。虽然细胞衰老已经被广泛地 在正常和病理状态下进行的研究，对癌症的研究几乎完全集中在成纤维细胞和 乳腺癌和前列腺癌模型中骨髓基质细胞的衰老。几乎没有 细胞衰老在脑肿瘤促进或治疗反应中的作用的研究 关注细胞衰老中的性别差异。我们有两个具体目标，我们将在以前的基础上再接再厉 成功地利用我们广泛验证的模型系统来研究GBM的性别差异 发展起来的。我们将应用创新的基因组技术来确定性别差异在p21中的作用。 和Rb对衰老的诱导作用，并将决定Brd4和性别特异性表观遗传学 是星形胶质细胞和基底膜细胞衰老和衰老相关分泌的性别差异所必需的 表型。

Abstract In the next year, approximately 22,000 Americans will develop glioblastoma (GBM) and nearly the same number will die from it. Further, we can reliably predict that of the 22,000 new cases, 8,500 will be in females while the remaining 13,500 cases will be in males. Moreover, while the median survival for female GBM patients next year is expected to be between 17 and 22 months, for males it will be closer to 16 months. The molecular bases for these consistent and significant sex differences in incidence and survival are unexplained. In the absence of an explanation, it is impossible to fully know what the implications of sex differences are for modeling GBM in the laboratory and for treating GBM in the clinic. Identifying targetable mechanisms underlying sex differences in survival are the focus of this project, and our goal is to improve outcomes for all GBM patients. Building on our published and preliminary studies supported during the prior funding period of this RO1, we now hypothesize that sex differences in cellular senescence contribute to the sex disparity in glioblastoma (GBM) incidence and survival. As radiation or chemotherapy induced senescence is a mechanism of stopping tumor growth, we will focus on the mechanisms that endow female cells with greater ability to undergo senescence than their male counterparts in response to DNA damage. While cellular senescence has been extensively studied in normal and pathological states, studies in cancer have focused almost exclusively on fibroblast and bone marrow stromal cell senescence in breast and prostate cancer models. There has been little to no investigation of the role that cellular senescence plays in brain tumor promotion or treatment response, or any focus on sex differences in cellular senescence. We have two Specific Aims in which we will build on our prior success and utilize the extensively validated model systems for studying sex differences in GBM that we developed. We will apply innovative genomic technologies to define the contributions of sex differences in p21 and Rb functions to the induction of senescence, and will determine whether Brd4 and sex-specific epigenetics are required for sex differences in astrocyte and GBM cell senescence and the senescence-associated secretory phenotype.