Treatment of gliomas with temozolomide: Rather at sunrise or sunset?

Treatment adapted to a specific time of the day is called chronotherapy or chronomedicine. In oncology, this approach has been considered of interest because the anti-cancer activity of some drugs may depend on circadian rhythms that exist in many organisms and may also be functionally relevant in tumor cells. Therefore, understanding the chronobiology of tumor cells has been an area of research over the last decades and a significant number of genes that are involved in the circadian biological rhythm have been identified and categorized as “clock genes”.¹ While many aspects of chronobiology have only been partially understood, it seems clear that clock systems allow cells to react to changes in the (micro)environment in order to optimize their biological function.

A quite large body of evidence suggests that the circadian clock in tumor cells is linked to DNA damage response mechanisms, which involve DNA damage checkpoints, nucleotide excision repair as well as survival pathways.² Based on these findings, therapeutic strategies aiming at disrupting clock genes and related pathways have been developed and explored in preclinical models. Among the genes involved in driving rhythmic gene expression under circadian control, the transcription factors CLOCK and BMAL1 were identified as central regulators, which modulate various biological functions.³ Beyond the direct targeting of components of the circadian clock, it has been hypothesized that the efficacy of anti-cancer drugs may be improved when administered at a specific time of the day. This concept, also referred to as chronochemotherapy, aims at optimizing pharmacokinetics and pharmacodynamics aspects by improving the drug’s absorption, metabolism, functional impact on cellular biology, and elimination. Beyond improving efficacy, drug administration at a specific time of the day may also reduce toxicity and improve the patients’ quality of life.

For several anti-cancer drugs, it was shown that their therapeutic activity depends on the time when they are administered. In line with this, the safety and tolerability of some chemotherapeutic agents are improved when given at specific times, eg, in the morning or evening. Based on these data, it might be of interest to explore the potential benefit of chronotherapy also in clinical neuro-oncology. There are preclinical data demonstrating that the activity of temozolomide may depend on the time of the day when it is administered. In a study with mouse glioma cells, temozolomide was most active when expression levels of the clock gene BMAL1 were high.⁴ Silencing of BMAL1 abrogated this effect. Data from a small retrospective study suggest that temozolomide dosing in the morning may be associated with higher efficacy and better outcomes.⁵ In this edition of Neuro-Oncology Practice, Damato et al report on the results of a prospective randomized phase II clinical study designed to determine the feasibility and safety of morning (before 10 am) vs evening (after 8 pm) dosing of temozolomide chemotherapy in glioma patients.⁶ They also tried to find preliminary efficacy signals that may favor 1 of the 2 dosing schedules. In this small randomized trial, they evaluated 35 glioma patients who received temozolomide either in the morning or in the evening. They found that timed dosing was feasible, and there were no significant differences in adverse effects. Obviously, the small sample size and the heterogeneous patient population did not allow conclusions on differences in efficacy. Accordingly, the authors state correctly that larger and sufficiently powered trials are needed to determine the superiority of 1 of the 2 dosing regimens. Given the limited success in the development of novel therapies for glioma patients, any improvement of the activity of the available drugs would be highly welcome.^7,8 Further clinical research would need to be accompanied by appropriate translational research to identify potential biomarkers that may reflect specific circadian rhythms. Furthermore, more insights into the underlying mechanisms may ultimately allow for patient stratification and personalized chronotherapy. Finally, the impact of temozolomide and other drugs on the circadian clock of tumor cells could be another biological aspect that warrants further research.

Conflict of interest statement. PR has received honoraria for lectures or advisory board participation from Bristol-Myers Squibb, Boehringer-Ingelheim, Covagen, Debiopharm, Midatech Pharma, MSD, Novartis, Novocure, QED, Roche.