Circadian rhythms in pediatric high-grade gliomas may contribute to treatment efficacy

Pediatric high-grade gliomas (pHGG) are highly invasive with poor survival outcomes. Timing of Temozolomide administration has been shown to affect survival of adult patients with glioblastoma. We investigated whether pHGGs express circadian genes rhythmically and whether underlying rhythms affect Temozolomide sensitivity. Circadian gene expression in pediatric gliomas was analyzed using PedcBioPortal. Immunoblotting was used to assess protein levels in patient-derived pHGG lines and in high- and low- grade (pLGG) glioma specimens. Rhythmic gene expression in pHGG lines was measured via qPCR, and Temozolomide efficacy was tested during peak versus trough Bmal1 expression. Patient data revealed significantly different mRNA expression in multiple circadian genes between pHGGs and pLGGs, including higher Bmal1 expression in pHGG specimens and lower Rev-Erbα expression. Significantly higher BMAL1 and CLOCK protein levels and lower REV-ERBα were present in pHGG versus pLGG tissue specimens. Our three pHGG lines displayed rhythmic Bmal1 and Rev-Erbα expression post-synchronization. We found significantly decreased proliferation when Temozolomide was applied during trough versus peak Bmal1 expression. The positive arm of the circadian clock appears upregulated in pHGGs compared to pLGGs. Pediatric HGGs rhythmically express circadian genes and exhibit differential Temozolomide sensitivity based on timing of administration.