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Advancing Clinical Response Against Glioblastoma: Evaluating SHP1705 CRY2 Activator Efficacy in Preclinical Models
Background:
It has been reported that circadian clock components, Brain and Muscle ARNT-Like 1 (BMAL1) and Circadian Locomotor Output Cycles Kaput (CLOCK), are uniquely essential for glioblastoma (GBM) stem cell (GSC) biology and survival. Consequently, we developed a novel Cryptochrome (CRY) activator SHP1705, which inhibits BMAL1-CLOCK transcriptional activity.
Methods:
We analyzed buffy coats isolated from Phase 1 clinical trial subjects' blood to assess any changes to circadian, housekeeping, and blood transcriptome-based biomarkers following SHP1705 treatment. We utilized GlioVis to determine which circadian genes are differentially expressed in non-tumor versus GBM tissues. We employed in vitro and in vivo methods to test the efficacy of SHP1705 against patient-derived GSCs and xenografts in comparison to earlier CRY activator scaffolds. Additionally, we applied a novel-REV-ERB agonist SR29065, which inhibits BMAL1 transcription, to determine whether targeting both negative limbs of the circadian transcription-translation feedback loop (TTFL) would yield synergistic effects against various GBM cells.
Results:
SHP1705 is safe and well-tolerated in Phase I clinical trials. SHP1705 has increased selectivity for the CRY2 isoform and potency against GSC viability compared to previously published CRY activators. SHP1705 prolonged survival in mice bearing GBM tumors established with GSCs. When combined with the novel REV-ERB agonist SR29065, SHP1705 displayed synergy against multiple GSC lines and differentiated GSCs (DGCs).
Conclusions:
These demonstrate the efficacy of SHP1705 against GSCs, which pose for GBM patient outcomes. They highlight the potential of novel circadian clock compounds in targeting GBM as single agents or in combination with each other or current standard-of-care.
Key Points:
SHP1705 is a novel CRY2 activator that has shown success in Phase 1 safety trialsSHP1705 has a significantly improved efficacy against GSCs and GBM PDX tumorsNovel REV-ERB agonist SR29065 and SHP1705 display synergistic effects against GSCs.
Importance Of The Study:
CRY2 is decreased in GBM tissues compared to CRY1 suggesting that promoting CRY2 activity will be an efficacious GBM treatment paradigm. SHP1705, a CRY2 activator that has shown success in Phase 1 safety trials, has significantly improved preclinical efficacy. Novel REV-ERB agonist SR29065 displays synergistic effects against diverse GBM cells.
Insights
A novel CRY2 activator, SHP1705, shows safety and efficacy against glioblastoma stem cells (GSCs) in early trials. Combination therapy with SR29065 demonstrates synergistic effects, highlighting potential new GBM treatments.
Area of Science:
- Neuro-oncology
- Chronobiology
- Cancer Therapeutics
Background:
- Circadian clock components BMAL1 and CLOCK are crucial for glioblastoma stem cell (GSC) survival.
- SHP1705 is a novel Cryptochrome (CRY) activator designed to inhibit BMAL1-CLOCK activity.
Purpose of the Study:
- To evaluate the safety and efficacy of SHP1705 in targeting GSCs.
- To investigate the synergistic effects of SHP1705 in combination with a REV-ERB agonist (SR29065).
Main Methods:
- Phase 1 clinical trials assessed SHP1705 safety and biomarker changes.
- In vitro and in vivo studies tested SHP1705 efficacy against patient-derived GSCs and xenografts.
- GlioVis was used to analyze differential gene expression in GBM tissues.
Main Results:
- SHP1705 is safe and well-tolerated in Phase 1 trials, with enhanced potency against GSCs compared to prior activators.
- SHP1705 prolonged survival in mouse models of GBM.
- Combination therapy with SR29065 showed synergistic anti-GSC effects.
Conclusions:
- SHP1705 demonstrates significant preclinical efficacy against GSCs and GBM xenografts.
- Targeting the circadian TTFL with compounds like SHP1705 and SR29065 offers a promising therapeutic strategy for GBM.
