Implications of Circadian Clock Control on Glioblastoma

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PROJECT SUMMARY/ABSTRACT Despite being thoroughly characterized, glioblastoma multiforme (GBM) remains one of the most common malignant primary brain tumors. Currently, patient prognosis has remained poor in that treatment for GBM has only moderately improved survival rates and quality of life even with the employment of aggressive multimodal therapies. The unique heterogeneous genetic, epigenetic, and microenvironmental features of GBM and the brain make tumors resistant to treatments that have otherwise been highly effective in treating cancers of other tissues. In particular, GBM contains cancer stem cells, termed glioblastoma stem cells (GSCs), that are self- renewing and tumorigenic, thereby supporting the progression and growth of the primary tumor even after surgical resection. GSCs have the ability to actively remodel the tumor microenvironment and receive maintenance cues from their surroundings. In recent published studies from our laboratory, GSCs have been found to display unique circadian rhythms and dependence on core circadian clock transcription factors, Brain and Muscle ARNT-Like 1 (BMAL1), otherwise known as Aryl Hydrocarbon Receptor Nuclear Translocator Like (ARNTL), and Circadian Locomotor Output Cycles Kaput (CLOCK). This dependence was not observed in normal neural cells nor differentiated glioblastoma cells (DGCs) and is consistent with associations between the circadian rhythm and increased likelihood of tumor development. Loss of BMAL1 or CLOCK in GSCs induced cell cycle arrest, apoptosis, attenuation of mitochondrial metabolic function, and reduced expression of the tricarboxylic acid (TCA) cycle enzymes and stemness genes, such SOX2, OLIG2, and MYC. Additionally, novel small molecule agonists and stabilizers of two independent negative core clock regulators, Cryptochrome 1/2 (CRY1/2) and REV-ERBa/b (REV-ERBs), were found to be able to downregulate stem cell regulators and reduce GSC growth. In this study, I intend to elucidate the mechanisms in which epigenetic machineries, in particular protein arginine methyl transferases (PRMTs), regulate transcription of circadian clock oscillators to promote stemness and proliferation abilities of GSCs. I also aim to determine the efficacy of small molecule CRY stabilizers and REV-ERB agonists, both independently and in combination with each other, in targeting GSCs as novel GBM therapies. My findings will illuminate the epigenetic regulation of circadian clock components in the context of GSC maintenance and progress a preclinical model for GBM treatment via pharmacological targeting of the circadian clock.