# Characterization of circadian rhythms in Glioblastoma multiforme and investigation of chronotherapy as a novel therapy to prolong patient survival

> **NIH NIH F31** · WASHINGTON UNIVERSITY · 2020 · $31,446

## Abstract

Project Summary
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.

## Key facts

- **NIH application ID:** 9990347
- **Project number:** 1F31CA250161-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** ANNA DAMATO
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $31,446
- **Award type:** 1
- **Project period:** 2020-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9990347

## Citation

> US National Institutes of Health, RePORTER application 9990347, Characterization of circadian rhythms in Glioblastoma multiforme and investigation of chronotherapy as a novel therapy to prolong patient survival (1F31CA250161-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9990347. Licensed CC0.

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