Glioblastoma multiforme (GBM) is the most common primary adult brain tumor diagnosed, with a 15-month prognosis using current standard of care treatment which includes chemotherapy with Temozolomide (Temodar, TMZ). Chronotherapy, the practice of considering time of day in treating a disease, has been shown to improve outcome in several cancers such as colorectal cancer and acute lymphoblastic leukemia, but has never been applied to GBM. Our previous work on a cultured murine mesenchymal GBM cell line showed a time-of-day dependent maximum in DNA double-strand breaks, activation of the apoptotic pathway, and cell death corresponding with the peak of Bmal1 and trough of Per2 expression, two core clock genes. Our preliminary data demonstrate that intracranial GBM tumors have circadian rhythms in gene expression in vivo that can be monitored chronically throughout disease progression. Most notably, our pilot data show that tumor rhythms in gene expression align with those of the host, leading to reversed patterns in tumor gene expression in a reversed light/dark cycle and free-running patterns that align with the host in constant darkness. This proposal will evaluate the hypothesis that GBM tumors have circadian rhythms in vivo that entrain to the host and that those daily rhythms can be leveraged using chronotherapy to improve survival. To address this hypothesis, this proposal will further assess if GBM tumors align with host daily rhythms in vivo as a function of changing light schedule, as described, and circadian genotype by implanting an arrhythmic tumor in a rhythmic mouse and a rhythmic tumor in an arrhythmic mouse and measuring changes in tumor growth rate, as well as synchrony between the host and tumor, according to circadian genotype (Aim 1). Furthermore, this proposal will determine differences in tumor cell death and host survival depending on time of day of TMZ dosing by measuring the effect of TMZ on daily rhythms in gene expression in both the host and tumor, as well as the effect of TMZ on tumor size reduction and severity of hematological toxicity (Aim 2). This proposal will improve outcome for patients with GBM for the first time in 20 years by maximizing tumor destruction while minimizing side effects by personalizing treatment based on patient sex and ideal time of day to treat. It will also serve as an important next step in achieving high-throughput screening for the optimal time to treat diseases beyond Glioblastoma.
Glioblastoma (GBM) is a deadly disease and there has been little improvement in therapy since Temozolomide became the standard of care in 1999. We demonstrated that timing chemotherapy in a cellular model of GBM to coincide with the daily peak expression level of a core clock gene, Bmal1, results in increased DNA damage and cell death, potentially conferring a therapeutic advantage. The experiments proposed here will connect the bench to the bedside by investigating mechanisms of tumor circadian rhythms in vivo and how they impact the efficacy of chemotherapy by analyzing the effects of the timed treatment as a function of biological factors such as sex and chronotype, maximizing anti-tumor effects and minimizing side effects of chemotherapy in treating an otherwise dismal disease.
