Project Summary This proposal tests the fundamental hypothesis that daily rhythms in neuronal activity promote growth of brain cancers and provide a temporal therapeutic window during which the efficacy of treatments may be substantially optimized, and novel targets discovered. 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 with and without intrinsic clock function, and in which recipient mice have been genetically engineered to allow control of diurnal cycles in neuronal activity, hormone signaling or rest-wake behavior. We will test in mice how human and mouse GBM cells integrate into the host’s circadian system to drive proliferation. We will evaluate treatments targeting the tumor or host circadian systems for their ability to slow tumor progression. Results from these experiments should reveal a role for sex differences in circadian rhythms that affect tumor growth. Success in these studies will advance our basic understanding of GBM biology and will provide critical information for the translational application of chronotherapy to GBM care.