Chronotherapy for glioblastoma

项目摘要 这项提议验证了一个基本假设，即脑肿瘤的昼夜节律提供了一个 时间治疗窗，在该时间治疗窗期间，标准治疗的功效可以被 大幅优化。定时化疗或时间疗法， 在结直肠癌和白血病中的作用，但从未在脑肿瘤中进行过评估。这里我们 基于令人兴奋的初步数据，我们已经证明， 替莫唑胺（TMZ），一种用于胶质母细胞瘤（GBM）的已确立的化疗剂， 通过一天中给药的时间进行调节。这些发现表明， 已经有办法显著改善这种令人沮丧的疾病的结果。在这 我们将利用新的GBM颅内异种移植模型，其中肿瘤细胞具有 被改造成肿瘤昼夜节律时间的报告者，其中受体小鼠 被基因改造成代表四种不同的行为昼夜变化模式， 或生理时钟类型。我们将在体内测试GBM细胞是否保持稳定的昼夜节律， 无论这些是独立的还是由宿主携带的，使用TMZ治疗是否是最好的 优化肿瘤或宿主昼夜节律，以及消融是否具有治疗价值 肿瘤昼夜节律这些研究的成功将促进我们对GBM的基本认识 昼夜节律生物学，并将提供关键信息的翻译应用 GBM护理的时间疗法。

Project Summary This proposal tests the fundamental hypothesis that circadian rhythms in brain tumors provide a temporal therapeutic window during which the efficacy of standard treatments may be substantially optimized. Timed delivery of chemotherapy, or chronotherapy, has an established role in colorectal cancer and leukemia but has never been evaluated in brain tumors. Here we build on exciting preliminary data in which we have demonstrated that the efficacy of Temozolomide (TMZ), an established chemotherapeutic for glioblastoma (GBM) is substantially modulated by the time of day when it is administered. These findings suggest that we may already have the means of significantly improving outcome from this dismal disease. In this proposal we will utilize novel intracranial xenograft models of GBM in which tumor cells have been engineered to serve as reporters of tumor circadian time, and in which recipient mice have been genetically engineered to represent four different patterns of diurnal variations in behavior, or chronotype. We will test in vivo, whether GBM cells maintain stable circadian rhythms, whether these are independent or entrained by the host, whether treatment with TMZ is best optimized to tumor or host circadian rhythm and whether there is therapeutic value in ablating tumor circadian rhythm. Success in these studies will advance our basic understanding of GBM circadian biology and will provide critical information for the translational application of chronotherapy to GBM care.