Date of Award
Doctor of Philosophy (PhD)
The safety and efficacy of multiple cancer chemotherapeutics can vary as a function of when during the day they are delivered. This study aimed to improve the treatment of glioblastoma multiforme (GBM), the most common brain cancer, by testing the efficacy of the DNA alkylator Temozolomide (TMZ) on GBM in vitro and in vivo as a function of time of day. We found cell-intrinsic, daily rhythms in susceptibility of GBM tumor cells (mouse astrocytes deficient in NF1 and p53 signaling) to TMZ in vitro. The greatest TMZ-induced DNA damage response, activation of apoptosis and growth inhibition, occurred near the peak expression of the core clock gene Bmal1 in cultured GBM cells. Deletion of Bmal1 abolished rhythmic circadian clock gene expression and circadian rhythms in TMZ-induced activation of apoptosis and growth inhibition in GBM tumor cells in vitro. Taken together, these data suggest an important role for the core molecular clock in regulating the tumor cell-intrinsic response to TMZ-induced DNA damage. These results may be important broadly for how we design TMZ and other DNA damaging approaches to GBM treatment.
Chair and Committee
Joshua Rubin, Erik Herzog
Paul Taghert, Katherine Weilbaecher, Zhongsheng You,
Slat, Emily A., "Circadian Regulation of Temozolomide Sensitivity in Glioblastoma" (2018). Arts & Sciences Electronic Theses and Dissertations. 1581.