Herzog, Erik D.

Glioblastoma (GBM) is an aggressive brain tumor that often progresses despite resection and treatment. Timely and continuous assessment of GBM progression is critical to expedite secondary surgery or enrollment in clinical trials. However, current progression detection requires costly and specialized MRI examinations, which, in the absence of new symptoms or signs, are usually scheduled every 2–3 months. Here, we hypothesized that changes in daily activity are associated with GBM growth and disease progression. We found that wheel-running activity in GBM-bearing mice declined as tumors grew and preceded weight loss and circadian breakdown by over a week. Temozolomide treatment in the morning, but not evening, significantly reduced tumor size and restored daily locomotion in mice. In a pilot study of 6 patients with GBM wearing an actigraphy watch, wrist movement provided a feasible and continuous longitudinal indicator of daily activity with 1-minute resolution. After tumor resection and radiation, daily activity declined in 2 patients 19 and 55 days before detection of progression by MRI but did not change for the 4 patients with stable disease. These results suggest that daily activity tracking using wearable devices may serve as a real-time indicator and potential monitoring tool for GBM progression and treatment efficacy.

Abstract Glioblastoma (GBM) is the most common primary tumor in adults with a median survival of 15 months post-treatment. GBM incidence and progression depends on sex, with reports of 1.6x increased incidence and 6-month shorter overall survival in males, compared to females. Regardless of sex, the standard of care for GBM patients includes surgical resection, followed by chemotherapy and radiotherapy, and often dosing of the synthetic glucocorticoid Dexamethasone (DEX) to reduce brain edema post-treatment. Our lab recently found that DEX can suppress or promote GBM growth depending on the time of day the treatment is administered. Because glucocorticoid secretion depends on circadian time and sex, we tested whether endogenous glucocorticoids regulate sex differences in GBM growth. We transduced a murine chromosomal male or female GBM cell line (Nf1-/-DNp53 XX or XY) with a transcriptional luciferase reporter of the circadian clock gene Per2 (Nf1-/-DNp53-P2L). These cells were next treated with DEX at the daily peak or trough of Per2 expression and growth was measured 48 hours post-treatment. We found that administering DEX at peak Per2 suppresses growth in males, while administering DEX at trough Per2 promotes growth in both males and females. We then knocked-down the glucocorticoid receptor (GR) using an shRNA lentiviral construct in two GBM cell models (GL261 and LN229) and implanted WT or GR-KD cells into the basal ganglia of male and female mice. Loss of GR in GBM cells significantly suppressed GBM growth, especially in male mice, as evidenced by postmortem Ki67 staining. These results suggest that GBM growth in males may be more sensitive to endogenous glucocorticoids, and that sensitivity varies with time of day. This work will inform future personalized circadian interventions to improve GBM patient outcomes. Supported by NIH grant R01NS134885.

High-grade gliomas, like glioblastoma multiforme (GBM), are the most common malignant brain tumors in adults and are treated with the chemotherapy drug temozolomide (TMZ). In humans, a retrospective analysis of patients’ overall survival suggests that morning dosing may confer a benefit over evening dosing. Circadian variation in O6-methylguanine-DNA methyltransferase (MGMT) gene expression and promoter methylation has been implicated in increased tumor cell sensitivity to TMZ in the morning. Although patient compliance with timed oral administration of TMZ was high in a prospective trial, it is not known whether differences in daily sleep patterns of patients impact the biological time of drug administration or overall survival. Using wrist actigraphy collected from 10 high-grade glioma patients, we quantified the moment of oral TMZ delivery in terms of wall clock time and internal biological time during the months after surgical tumor resection. We found that variation of daily rhythms within and between individuals caused dosing times to vary more in their internal biological time than wall clock time so that, for example, some doses taken by patients assigned for the evening (2000 h) were closer to the patient’s internal biological morning. We conclude that wrist actigraphy provides a reliable and non-invasive estimate of personal circadian time that could improve efficacy and precision of TMZ delivery. These findings may inform personalized circadian medicine and optimized times for TMZ delivery in the clinic.