Chronotherapy for glioblastoma

项目摘要 这一提议检验了脑肿瘤昼夜节律提供 临时治疗窗口，在此期间标准治疗的疗效可能 进行了实质性优化。定时化疗或计时疗法已经确立了 在结直肠癌和白血病中的作用，但从未在脑肿瘤中被评估过。在这里我们 建立在令人兴奋的初步数据基础上，我们已经在这些数据中证明了 替莫唑胺(TMZ)是一种公认的治疗胶质母细胞瘤(GBM)的化疗药物 由每天给药的时间调节的。这些发现表明，我们可能 已经有办法显著改善这种令人沮丧的疾病的结果。在这 建议我们将利用新型的异种颅内基底膜移植模型，在这种模型中，肿瘤细胞 被设计成作为肿瘤昼夜节律的报告者，在其中受体小鼠 通过基因工程来代表行为的四种不同的日变化模式， 或年代型。我们将在体内测试GBM细胞是否保持稳定的昼夜节律， 无论它们是独立的还是被宿主缠绕的，用TMZ治疗都是最好的 对肿瘤或宿主昼夜节律进行优化，以及消融是否有治疗价值 肿瘤昼夜节律。这些研究的成功将促进我们对GBM的基本理解 昼夜节律生物学，并将为翻译应用提供关键信息 从时间疗法到GBM护理。

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.