Small molecule circadian clock compounds display therapeutic potential in targeting glioblastoma stem cells

Abstract Glioblastoma multiforme (GBM) is the most common primary brain tumor, claiming the lives of roughly 10,000 Americans each year. Despite being the first cancer analyzed through the Cancer Genome Atlas, treatment success remains minimal, resulting average survival time of patients is 15 months following diagnosis and a five-year survival rate is 6.8%. One of the major challenges in treating GBM is the presence of GBM stem cells (GSCs) that are resistant to temozolomide (TMZ) chemotherapy and radiation, which is part of the current standard of care for GBM following maximal surgical resection. We found, however, that GSCs have a unique dependence on core circadian clock proteins, Brain and Muscle ARNTL-Like 1 (BMAL1) and Circadian Locomoter Output Cycles Protein Kaput (CLOCK), which is not observed in differentiated GBM cells or normal neuronal stem cells. Here we explore the use of novel small molecule circadian clock compounds that either lower BMAL1 transcription (REV-ERB agonists) or inhibit BMAL1::CLOCK heterodimer transcriptional activity (Cryptochrome (CRY) stabilizers or Casein Kinase (CK) 1/2 inhibitors) in targeting GSCs in in vitro patient derived cell lines and in in vivo GBM patient-derived xenograft (PDX) models. GSCs display increased sensitivity to clock compounds at single agent and combinations of clock compounds compared to non-cancerous cells, U2OS human osteosarcoma cells, and differentiated GSCs. Additionally, clock compounds are significantly more effective in targeting GSCs than TMZ. The clock compound SHP1705 increased over survival and delayed tumor growth in GBM PDX models. These results highlight the therapeutic potential small molecule circadian clock compounds have against GBM as both a single agent and adjuvant to existing therapies by specifically targeting the GSC population. Citation Format: Priscilla Chan, Lian Wu, Anahit Hovsepyan, Seda Mkhitaryan, Gevorg Karapetyan, Khalid Shah, Hiroaki Wakimoto, Theodore Kamenecka, Laura A. Solt, Jamie Cope, Rex A. Moats, Tsuyoshi Hirota, Jeremy N. Rich, Steve A. Kay. Small molecule circadian clock compounds display therapeutic potential in targeting glioblastoma stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 505.