Review: therapeutic approaches for circadian modulation of the glioma microenvironment

Abstract

High-grade gliomas are malignant brain tumors that are characteristically hard to treat because of their nature; they grow quickly and invasively through the brain tissue and develop chemoradiation resistance in adults. There is also a distinct lack of targeted treatment options in the pediatric population for this tumor type to date. Several approaches to overcome therapeutic resistance have been explored, including targeted therapy to growth pathways (ie. EGFR and VEGF inhibitors), epigenetic modulators, and immunotherapies such as Chimeric Antigen Receptor T-cell and vaccine therapies. One new promising approach relies on the timing of chemotherapy administration based on intrinsic circadian rhythms. Recent work in glioblastoma has demonstrated temporal variations in chemosensitivity and, thus, improved survival based on treatment time of day. This may be due to intrinsic rhythms of the glioma cells, permeability of the blood brain barrier to chemotherapy agents, the tumor immune microenvironment, or another unknown mechanism. We review the literature to discuss chronotherapeutic approaches to high-grade glioma treatment, circadian regulation of the immune system and tumor microenvironment in gliomas. We further discuss how these two areas may be combined to temporally regulate and/or improve the effectiveness of immunotherapies.

Pharmacological Modulation of the Cytosolic Oscillator Affects Glioblastoma Cell Biology

“…Median patient survival after diagnosis is 12–15 months, there are no full curative therapies and less than 5% of patients survive 5 years (reviewed in (Wagner et al 2021a )). Recent evidence in the field shows that circadian clock function should be considered a novel target to design new therapeutic strategies or improve the current approaches to treat high-grade gliomas (reviewed in Wagner et al 2021a ; Nettnin et al 2023 )) (Slat et al 2017 ; Trebucq et al 2021 , 2024 ). We thus investigated the effects of pharmacological modulation of the circadian clock in terms of cell viability, proliferation, and migration on GBM cultures using the CK1ε/δ inhibitor (PF670462), the GSK-3 inhibitor (CHIR99021), and the CRY protein stabilizer (KL001).…”