Ivie Izekor

Introduction: Glioblastoma is an aggressive type of cancer that either occurs in the brain or spinal cord with a low prognosis and limited success in survival.⁵ Efforts to identify specific environment and occupational risk factors have been inconclusive.⁶ Pathogenesis comes from the mutations affecting major signaling pathways such as citric acid cycle, notch pathway, rb protein signaling etc.⁷ Despite fatality, treatments are limited to surgeries and chemotherapy. New therapy involves using chronotherapy which utilizes the knowledge of circadian rhythms as principal coordinators to modulate gene expression and cell regeneration in slowing the growth of GBM cells. Emerging studies focus on modifying circadian related transcription factors such as CLOCK BMAL, p38 or differential time response to drug therapy. In this abstract, temporal regulation will be discussed as a potential chemotherapeutic target for GBM patients. Methods:  Experiments monitored the circadian clock activity of the BMAL1 promoter using a luciferase reporter. The circadian regulators were knocked down/ repressed and cell cycle progression and apoptosis was closely monitored.¹ Another study,  the ishCLOCK system was used to inducibly deplete CLOCK in both GSC272 and GSC20 tumors in SCID mice to reveal the dependence of GBM cells on CLOCK. OLFML3 deletion was tracked as a novel chemokine highly associated with CLOCK and BMAL1 that can affect GBM cell survival.² To get the time dependent effects of p38 MAPK inhibition, using VX-745l as an inhibitor on HA and IM3 glial cells, Boyden chamber assays were utilized to display their respective invasiveness following chronotherapeutic treatment.³ Lastly, some studies were retrospective and did statistical analysis of 166 diagnosed glioblastoma patients prescribed tenzomolide treatment.⁴ The study used a restricted mean interval time (RMST) method to assess differences in OS( Overall Survival)between TMZ AM and PM administration.⁴  Results: Experiments revealed that BMAL1 and CLOCK help maintain metabolic homeostasis due their association with regulation of bioenergetics e.g. glycolysis and TCA cycle in glioblastoma cells.¹ Succinate dehydrogenase shows high dependence on BMAL1 and CLOCK and loss of these factors lead to repression of GSC proliferation.¹ It was revealed that 11 genes tracked positively with CLOCK expression but OLFML3 showed the most significant correlation with chemotaxis and reduced CLOCK depletion in GSC20.² Time of day reduction of cell invasiveness is possible with the application of VX-745( a p38 inhibitor) because of p38 rhythmic activity  in glioma cells.³ The invasiveness was reduced when the inhibitor was administered at the time of trough levels of phosphorylated p38 MAPK.³ In the retrospective study, Patients who took Temozolomide in the morning displayed longer overall survival compared to those who got it administered in the evening.⁴  Conclusion: Glioblastoma cells exhibit unique chromatin landscapes that reprogram the output of BMAL1 and CLOCK dependent transcription regimes and these transcription factors play a critical role in maintaining the metabolic states that support cancer growth. Targeting genes with close correlation to BMAL-CLOCK  such as depletion of OLFML3 can lead to an increase in survival. Although p38 toxicity of p38 MAPK limits their clinical use, inhibition of the p38 MAPK pathway with temporal considerations may be more effective and less toxic.  Established cancer therapy such as Temozolomide and Bortezomib chemotherapy efficiency can be enhanced when administered with chronological considerations. This has the potential to increase patient overall survival.It is transparent that the science of circadian rhythm can lead to broad approaches in the prevention and management of a disease. With recent advancements in the field of chronotherapy and the stagnant improvement of GBM patient survival, it has potential to be a chemotherapeutic target.

1. Dong Z, Zhang G, Qu M, et al. Targeting Glioblastoma Stem Cells through Disruption of the Circadian Clock. Cancer Discov. 2019;9(11):1556-1573. doi:10.1158/2159-8290.CD-19-0215
2. Chen P, Hsu WH, Chang A, et al. Circadian Regulator CLOCK Recruits Immune-Suppressive Microglia into the GBM Tumor Microenvironment. Cancer Discov. 2020;10(3):371-381. doi:10.1158/2159-8290.CD-19-0400
3. Goldsmith CS, Kim SM, Karunarathna N, et al. Inhibition of p38 MAPK activity leads to cell type-specific effects on the molecular circadian clock and time-dependent reduction of glioma cell invasiveness [published correction appears in BMC Cancer. 2019 Jan 23;19(1):101]. BMC Cancer. 2018;18(1):43. Published 2018 Jan 10. doi:10.1186/s12885-017-3896-y
4. Chen P, Hsu WH, Chang A, et al. Circadian Regulator CLOCK Recruits Immune-Suppressive Microglia into the GBM Tumor Microenvironment. Cancer Discov. 2020;10(3):371-381. doi:10.1158/2159-8290.CD-19-0400
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