MOUSE MODELS FOR EXPLORING THE DEVELOPMENTAL ORIGINS OF SEX DIFFERENCES IN GLIOBLASTOMA

摘要 尽管经过数十年的研究，治愈胶质母细胞瘤（GBM）仍然是一个棘手的问题。新的方法 在本提案中，我们将利用GBM的性别差异来产生新的见解， 控制胶质瘤发生和治疗反应的机制。像许多其他癌症一样，GBM发生率更高， 男性多于女性，无论年龄或地理位置如何。性别差异的原因 癌症的发病率和存活率在很大程度上是未知的，但必须追溯到性的作用。 染色体，以及性激素的长期表观遗传和急性效应。了解性如何 影响癌症的发病率和结果将是至关重要的发展真正个性化的精度 癌症治疗的医学方法，因为考虑病人的性别是其基本组成部分， 个性。在这个提议中，我们将利用性别差异来创造一种类似于马拉克斯的效果， GBM生物学中不明显的元素将被揭示。我们最近使用这种方法发现了细胞 在间充质GBM模型中，恶性转化阈值存在内在性别差异。我们 假设癌症易感性和抗性的基本机制在于 性别差异的生物学为了完成这些研究，我们将建立一个新的模型系统来检查性别 GBM的差异。我们有两个具体目标。在第一个目标中，我们将调整我们的间充质GBM模型 支持分析性分化模式中的早期事件如何对致癌事件作出反应， 在雄性和雌性星形胶质细胞中建立不同的转化阈值。我们将利用这四个- 核心基因型模型的性别差异和地址的假设， 染色体互补和性激素的表观遗传效应影响肿瘤发生。第二个目标 我们将使用相同的模型来解决关键的转化科学目标，即确定这些目标中的哪一个 发育因素是对普通和实验性化疗药物反应的性别差异的基础。 这些研究共同构成了GBM生物学的开创性方法。这些研究的成功具有真实的 潜在的新见解具有重大的翻译意义，因为我们努力实现个性化 GBM和其他癌症的精确治疗方法。

Abstract Despite decades of research, curing glioblastoma (GBM) remains an intractable problem. Fresh approaches are needed and in this proposal we will use sex differences in GBM to generate novel insights into mechanisms that control gliomagenesis and treatment responses. Like many other cancers, GBM occurs more frequently in males than females, regardless of age or geographical location. The reason(s) for sex differences in cancer incidence and survival are largely unknown but must be traceable to the actions of sex chromosomes, and the long-term epigenetic and acute effects of sex hormones. Understanding how sex imparts affects cancer incidence and outcome will be essential for development of truly personalized precision medicine approaches to cancer treatment, as accounting for patient sex is a fundamental component of their individuality. In this proposal we will use sex differences to create a parallax-like effect, in which previously unapparent elements of GBM biology will be revealed. We recently used this approach and discovered cell intrinsic sex differences exist in thresholds for malignant transformation in a model of mesenchymal GBM. We hypothesize that fundamental mechanisms of cancer susceptibility and resistance lie within the biology of sex differences. To complete these studies we will build a new model system to examine sex differences in GBM. We have two specific aims. In the first aim we will adapt our model of mesenchymal GBM to support the analysis of how early events in sexual differentiation pattern responses to oncogenic events and establish different thresholds for transformation in male and female astrocytes. We will make use of the four- core genotypes model of sex differences and address hypotheses regarding how differences in sex chromosome complement and the epigenetic effects of sex hormones affect tumorigenesis. In the second aim we will use the same model to address the critical translational science objective of determining which of these developmental factors underlies sex differences in response to common and experimental chemotherapeutics. Together these studies constitute a pioneering approach to GBM biology. Success in these studies has real potential for novel insights with substantial translational significance as we strive to implement personalized precision approaches to treatment for GBM and other cancers.