A series of preclinical studies show that a new compound, SHP1705, targets circadian clock proteins hijacked by glioblastoma stem cells, impairing the cancer cells’ ability to survive and grow.

SHP1705 is also the first clock-targeting compound to complete a phase 1 clinical trial, where it was found to be safe and well-tolerated in humans.

A summary of the research was published in the journal Neuro-Oncology.

Glioblastoma is the most common cancerous brain tumour in adults—and one of the most difficult to treat.

Most patients receive a combination of surgery, radiation and chemotherapy, but tumours typically return and resist further treatment.

Circadian clock proteins, which regulate the body’s sleep-wake cycle and other daily rhythms at the cellular level, offer a potential solution.

Glioblastoma cells hijack these proteins in order to replicate, so switching them off could slow or halt tumour growth.

“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 and co-director of the USC Norris Centre for Cancer Drug Development at the Keck School of Medicine of USC.

“If we can successfully target the circadian clock, these cells lose their ability to replicate.”

With partial funding from the National Institutes of Health, Kay and Jeremy Rich, MD, of the University of North Carolina at Chapel Hill, oversee an international research team that is developing a drug to target the hijacked circadian clock proteins.

Through a series of biochemical, cellular and animal studies, the researchers tested SHP1705’s ability to neutralise glioblastoma stem cells, finding it to be highly effective.

A phase 1 clinical trial led by Synchronicity Pharma, a biotechnology startup that Kay co-founded, showed that SHP1705 was well-tolerated in humans.

Compared to the team’s earlier studies of clock-targeting compounds, SHP1705 is more potent and a better match for glioblastoma, Kay said.

“Scientists have studied glioblastoma for decades, but the prognosis and survival rates are still very dismal,” said Priscilla Chan, PhD, a postdoctoral researcher at the Keck School of Medicine and the study’s first author.

“If we can move the needle in any way, that would be fantastic for patients.”

Targeting glioblastoma cells

SHP1705 is known as a CRY activator because it increases the activity of cryptochrome (CRY) proteins inside cells.

CRY proteins then inhibit the cell’s circadian clock machinery.

Unlike earlier CRY activators studied by Kay’s team, SHP1705 specifically targets a version of the CRY protein known as CRY2.

CRY2 levels are unusually low in glioblastoma cells, making these cells more responsive to attempts to reactivate the protein.

By boosting CRY2 activity in glioblastoma cells, SHP1705 helps shut down the cancer cells’ circadian clock machinery, while leaving healthy brain cells—where CRY2 is already active—largely unaffected.

The researchers conducted a series of preclinical studies that tested SHP1705’s ability to fight glioblastoma stem cells, which are thought to drive tumour growth and recurrence.

They found that SHP1705 impaired cancer stem cells’ ability to survive, with minimal impact on healthy cells.

When they treated glioblastoma stem cells with other compounds developed to target clock proteins, none worked as well as SHP1705.

The tests included two lines of glioblastoma stem cells: one responsive to temozolomide (chemotherapy) treatment and one resistant to it.

SHP1705 targeted both, suggesting it could be effective against cancer cells that return after initial treatment.

Mouse studies further confirmed SHP1705’s potential, showing that a higher dose slowed tumour growth and extended survival.

In mice, SHP1705 also made cancer cells more likely to die after radiation treatment.

Combining SHP1705 with SR29065, a compound targeting another part of the circadian clock that was developed by Kay’s collaborators at the Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, produced even better results in several tests.

“The synergy we observed between these two compounds also shows great potential,” Kay said.

Finally, Synchronicity Pharma conducted a phase 1 clinical trial with 54 healthy volunteers, finding that SHP1705 was well-tolerated, with only minor side effects such as headache and nausea.

Testing SHP1705 with patients

The next step is a phase 2 clinical trial, where SHP1705 will be tested alongside existing treatments: surgery, chemotherapy and radiation.

The compound can be taken as a pill, so it adds minimal burden to patients already undergoing intensive treatment.

“Right now, the current standard of care does not address glioblastoma stem cells that drive the cancer’s recurrence,” Chan said.

“Our hope is that SHP1705 can help close that gap.”

Hijacked clock proteins not only play a role in glioblastoma stem cell replication, but appear to fuel tumour growth in other ways.

Research suggests they help suppress immune cell activity and promote blood vessel growth to support the tumour.

Kay, Chan and their team are now investigating ways to further target these proteins.

Source: Keck School of Medicine of USC