DDDR-07 - Targeting the circadian clock with small molecule compounds results in anti-tumor effects specifically in glioblastoma stem cells

Sunday, November 19, 2023

11:25 AM – 11:30 AM PT

Location: Room 109-110

Oral Abstract Presenter(s)

Priscilla Chan

University of Southern California
Los Angeles, California, United States

Author(s)

LW

Lian Wu

Department of Medicine, University of Pittsburgh Medical Center
Pittsburgh, California, United States
AH

Anahit Hovsepyan

Children's Hospital of Los Angeles
Los Angeles, United States
SM

Seda Mkhitaryan

Children's Hospital of Los Angeles
Los Angeles, United States
GK

Gevorg Karapetyan

Children's Hospital of Los Angeles
Los Angeles, United States
KS

Khalid Shah

Harvard Medical School
Boston, Massachusetts, United States
Hiroaki Wakimoto

Harvard Medical School
Boston, Massachusetts, United States
TK

Theodore M. Kamenecka

University of Florida
Jupiter, United States
LS

Laura A. Solt

University of Florida
Jupiter, United States
JC

Jamie Cope

Synchronicity Pharma
San Jose, United States
RM

Rex Moats

Children's Hospital of Los Angeles
Los Angeles, United States
TH

Tsuyoshi Hirota

Nagoya University
Nagoya, United States
JR

Jeremy N. Rich

University of Pittsburgh, Pennsylvania
St Louis, Pennsylvania, United States
SK

Steve A. Kay

University of Southern California
Los Angeles, United States

Glioblastoma multiforme (GBM) is the most common primary brain tumor, with an average survival time of less than one year following diagnosis. Treatment success remains challenging despite aggressive, multimodal current standard-of-care consisting of maximal surgical resection followed by concurrent temozolomide (TMZ) chemotherapy and radiation. The presence of GBM stem cells (GSCs) is thought to make treatment exceptionally difficult as they are highly invasive, resistant to chemoradiation, promote angiogenesis, support an immune suppressive environment, and can recapitulate the primary tumor following surgical resection. We have reported that GSCs, however, are dependent 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. In this study, we explore the anti-GSC effects of multiple families 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). Here we report that compared to compared to non-cancerous cells, U2OS human osteosarcoma cells, and differentiated GSCs (DGCs), GSCs display increased sensitivity to clock compounds at single agent and combinatory doses of clock compounds. Additionally, clock compounds are significantly more effective in targeting GSCs than TMZ and combinations of clock compounds with TMZ can lower TMZ IC₅₀ value in different GBM cell lines and types. Application of the CRY stabilizer SHP1705 in GBM PDX patient derived xenograft (PDX) models resulted in decreased tumor growth rate and increased survival time compared to vehicle control. These results highlight the therapeutic potential of circadian clock compounds as single agents, in combinations and as adjuvants to existing therapies by specifically targeting the GSC population in GBM.