Molecular basis for the impact of sex on brain tumorigenesis

摘要 在接下来的一年里，大约22，000名美国人将发展成胶质母细胞瘤（GBM）， 此外，我们可以可靠地预测，在22,000例新病例中，8,500例将是女性， 其余一万三千五百宗为男性。此外，虽然明年女性GBM患者的中位生存率 预计在17至22个月之间，男性将接近16个月。分子基础 这些在发病率和存活率方面的一致和显著的性别差异是无法解释的。在没有 解释，不可能完全知道性别差异对GBM建模的影响。 用于实验室和临床治疗GBM。确定性别差异的潜在目标机制 生存率是这个项目的重点，我们的目标是改善所有GBM患者的预后。充分发挥两国 在本RO 1的上一个资助期内发表和支持的初步研究，我们现在假设 细胞衰老的性别差异导致胶质母细胞瘤（GBM）的性别差异 发病率和生存率。由于放疗或化疗诱导的衰老是阻止肿瘤的机制 生长，我们将重点关注赋予雌性细胞更大的衰老能力的机制 比男性更容易受到DNA损伤。虽然细胞衰老已经被广泛地 在正常和病理状态下的研究，癌症研究几乎完全集中在成纤维细胞上， 乳腺癌和前列腺癌模型中的骨髓基质细胞衰老。几乎没有 研究细胞衰老在脑肿瘤促进或治疗反应中的作用，或任何 关注细胞衰老的性别差异。我们有两个具体的目标，我们将建立在我们以前的 成功并利用广泛验证的模型系统来研究GBM的性别差异， 开发我们将应用创新的基因组技术来确定p21中性别差异的贡献。 和Rb的功能，以诱导衰老，并将决定是否Brd 4和性别特异性表观遗传学 是星形胶质细胞和GBM细胞衰老和衰老相关的分泌功能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.