Researchers at the Keck School of Medicine of USC have found a compound that disrupts the internal clockwork of glioblastoma stem cells, showing safety in humans and promising results in a Phase I clinical trial. Results from the trial, published in Neuro-Oncology, focused on SHP1705, a compound that activates specifically CRY2, a chryptochrome protein, to suppress the transcriptional activity of BMAL1 and CLOCK, key components of the circadian clock machinery. These proteins regulate the body’s cellular rhythms but are hijacked in glioblastoma stem cells (GSCs) to promote tumor growth, therapy resistance, and recurrence.
“We have mounting evidence that clock proteins can be co-opted by brain cancer stem cells to fuel their growth,” said the study’s senior author, Steve A. Kay, PhD, university and provost professor of neurology, biomedical engineering, and quantitative computational biology at the Keck School of Medicine. “If we can successfully target the circadian clock, these cells lose their ability to replicate.”
The study is the first Phase I trial of a compound targeting the circadian clock machinery. It enrolled 54 healthy volunteers and demonstrated that the drug was safe and well-tolerated, with only minor side effects such as nausea and headache.
“To confirm the mechanism of action of SHP1705, we examined luciferase reporter activity following treatment with SHP1705. SHP1705 treatment resulted in increased repression of BMAL1-CLOCK transcriptional activity,” the researchers wrote in their paper. The investigation found that the compound reduced expression of BMAL1-CLOCK target genes like PER2 in glioblastoma stem cells, with minimal effects on non-cancerous cells. Protein thermal shift assays also revealed SHP1705’s preferential binding to CRY2 over CRY1, a key distinction given that CRY2 is underexpressed in glioblastoma cells.
The research built on earlier studies, which showed that BMAL1 and CLOCK play a role in the survival of glioblastoma stem cells. “The core clock protein BMAL1 has an increased chromatin-binding pattern that overlaps with marks of active transcription in GSCs compared to noncancerous neural stem cells,” the researchers wrote. These prior observations suggested that disrupting clock-controlled transcription might selectively impair GSCs without damaging healthy cells.
Compared to previous compounds targeting clock components, including KL001, SHP656, and SHP1703, SHP1705 demonstrated increased potency and isoform selectivity. In preclinical studies, SHP1705 impaired the viability of both chemotherapy-sensitive and -resistant GSC lines. In vivo mouse models confirmed that SHP1705 slowed tumor growth and extended survival. The mouse models also tolerated the compound without significant weight changes or toxicity.
A second compound, SR29065, developed by collaborators at the Herbert Wertheim UF Scripps Institute, targets another arm of the circadian feedback loop by acting as a REV-ERB agonist. When combined with SHP1705, the compounds showed synergy in multiple glioblastoma stem cell and differentiated cell lines.
Building on these positive data, the Keck team is now readying a Phase II clinical trial to test SHP1705 in glioblastoma patients in combination with standard treatments such as surgery, chemotherapy, and radiation, and could eventually be an important new treatment option.
“Right now, the current standard of care does not address glioblastoma stem cells that drive the cancer’s recurrence,” said first author Priscilla Chan, PhD, a postdoctoral researcher at Keck. “Our hope is that SHP1705 can help close that gap.”
The implications for clinical care are significant. By targeting the circadian clock machinery that GSCs rely on for survival, SHP1705 could suppress tumor recurrence and enhance the effects of existing therapies.
Despite this progress, the researchers said these early results should be considered with caution. Some glioblastoma and differentiated cell lines did not respond synergistically to the SHP1705 and SR29065 combination, particularly those resistant to temozolomide. This may reflect underlying differences in circadian protein expression among glioblastoma subtypes.
For their continuing research, the investigators plan to examine the effects of the two compounds on the glioblastoma tumor microenvironment, particularly as it relates to immune suppression and angiogenesis. They also plan to explore how timing drug administration, known as chronomedicine, might improve treatment outcomes.
“With increased understanding of how response to chemoradiation changes according to time-of-day administration, we can take advantage of different modalities of chronomedicine to improve upon GBM patient outcomes,” the researchers wrote.
