Abstract 669: Interrogating circadian clock compounds as an adjuvant to chemoradiation against GBM

Abstract

Abstract Despite the extensive efforts of researchers and physicians over the past two decades, glioblastoma (GBM) remains the most prevalent brain tumor type with a grim average survival time of 8 months following diagnosis irrespective of treatment. Additionally, the current standard-of-care has not changed from maximal surgical resection followed by concurrent chemoradiation from its establishment in 2005. One of the major challenges that limits progress in treating GBM is the presence of GBM stem cells (GSCs) that are highly invasive, reaching far past the tumor margins, are resistant to both chemotherapy and radiation, and can recapitulate the primary tumor following resection. Recent studies have found that GSCs, however, are highly sensitive to targeting of core circadian clock components, particularly positive regulators of the clock Brain and Muscle ARNTL-Like 1 (BMAL1) and Circadian Locomoter Output Cycles Protein Kaput (CLOCK). Here we employ the use of small molecule compounds that upregulate the activity of the negative regulators of the clock in order to suppress BMAL1::CLOCK transcriptional activity or repress BMAL1 transcription. We find that these compounds not only have a much more potent effect against GSCs compared to temozolomide (TMZ) chemotherapy but also, they display combination effect against both GSCs and differentiated GSCs (DGCs) when combined with TMZ. These results suggest that the blood brain barrier (BBB) penetrant circadian clock compounds can be utilized as an adjuvant to current GBM therapies as they can effectively target both the primary tumor cells and GSCs. Citation Format: Priscilla Chan, Qiulian Wu, Anahit Hovsepyan, Seda Mkhitaryan, Gevorg Karapetyan, Khalid Shah, Hiroaki Wakimoto, Theodore Kamenecka, Laura A. Solt, Jamie Cope, Tsuyoshi Hirota, Rex A. Moats, Jeremy N. Rich, Steve A. Kay. Interrogating circadian clock compounds as an adjuvant to chemoradiation against GBM [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 669.