Abstract 1754: Evaluating the synergism between circadian clock compounds with chemoradiation against GBM

Abstract The circadian clock has been associated with numerous diseases and, in recent years, been linked to every known cancer hallmark. In the case of glioblastoma (GBM), high expression of positive regulators of the clock, such as Brain and Muscle ARNT-Like 1 (BMAL1), has been linked to shorter survival time while high expression of the negative regulators of the clock confers longer survival time. Furthermore, BMAL1 and Circadian Locomotor Output Cycles Kaput (CLOCK) were found to be essential for GBM stem cell (GSC) proliferation, stemness, and metabolism. GSCs are typically resistant to chemoradiation and secrete factors that drive neoangiogenesis and immune suppression in the tumor microenvironment (TME). However, we found that GSCs are specifically sensitive to genetic and pharmacological perturbation of these core clock components. Consequently, in this study, we sought to explore the anti-GBM effects of chemoradiation in combination with the novel Cryptochrome (CRY) stabilizer SHP1705, which inhibits BMAL1 and CLOCK transcriptional activity, and the novel REV-ERB agonist SR29065, which inhibits BMAL1 transcription. SHP1705 has proven to be safe and well-tolerated in Phase I clinical trials and SR29065 is well-tolerated in mice without evidence of cytotoxicity. Our findings highlight the potential of small molecule circadian clock modulating compounds as a novel treatment paradigm that sensitizes resistant GBM cell populations to chemoradiation. Citation Format: Priscilla Chan, Yoshiko Nagai, Qiulian Wu, Jiarui Wang, Theodore Kamenecka, Laura A. Solt, Jamie Cope, Tsuyoshi Hirota, Jeremy N. Rich, Steve A. Kay. Evaluating the synergism between circadian clock compounds with chemoradiation against GBM [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1754.