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

摘要 尽管经过了几十年的研究，治疗胶质母细胞瘤(GBM)仍然是一个棘手的问题。新方法 在这个提案中，我们将利用GBM中的性别差异来生成对 控制胶质瘤发生和治疗反应的机制。像许多其他癌症一样，基底细胞癌更容易发生。 男性多于女性，不论年龄或地理位置。性别差异的原因(S) 癌症的发病率和存活率在很大程度上是未知的，但必须与性行为有关 染色体，以及性激素的长期表观遗传和急性影响。了解性爱是如何 传授影响癌症发病率和预后将是开发真正个性化的精确度所必需的 医学接近癌症治疗，因为考虑到患者的性别是其 个性。在这项提案中，我们将使用性别差异来创建视差效果，在此之前 GBM生物学中不明显的元素将会被揭示。我们最近使用了这种方法，发现了细胞 在间充质基底膜模型中，恶性转化阈值存在内在的性别差异。我们 假设癌症易感性和耐药性的基本机制存在于 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 在GBM上的差异。我们有两个具体目标。在第一个目标中，我们将采用我们的间充质基底膜模型 支持对性分化早期事件如何对致癌事件作出反应以及 为雄性和雌性星形胶质细胞建立不同的转化阈值。我们将利用这四项- 性别差异的核心基因分型模型和关于性别差异如何的假设 染色体互补和性激素的表观遗传效应影响肿瘤的发生。在第二个目标中 我们将使用相同的模型来解决关键的翻译科学目标，即确定其中哪些 发育因素是常见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生物学的一种开创性方法。这些研究的成功是真实的 随着我们努力实现个性化，具有重大翻译意义的新见解的潜力 治疗基底膜和其他癌症的精确方法。

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.