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.