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.
Temozolomide (TMZ) is the standard chemotherapy agent for patients with glioblastoma (GBM). Our recent publications indicate that appropriately timed TMZ treatment results in reduced adverse events, and greater suppression of GBM growth. We will test the hypothesis that morning TMZ treatment results in increased overall survival of mice with intracranial GBM through circadian modulation of the DNA repair pathway.
