A recent study conducted by researchers from the Keck School of Medicine of USC has shown that circadian clock proteins, which help coordinate changes in the body’s functions during the day, could have a role in the growth and spread of glioblastoma after the standard treatments used today, according to a press release.
This discovery further led to the identification of a small molecule drug called SHP656, which can eradicate the clock proteins and prove effective for the treatment of glioblastoma.
“This is a potent molecule that’s very exciting to us in terms of its potential for deployment against glioblastoma,” said Steve Kay, Ph.D., the senior author of the study.
“We’re now starting to march down the path of clinical drug development—turning this from a science story into a translational one,” added Kay.
Raising awareness about glioblastoma
Glioblastoma is an aggressive type of cancer that occurs in the brain or spinal cord. After being diagnosed, patients survive an average of only 15 months. Though it may develop at any age, it often affects older adults and leads to such symptoms as seizures, nausea, vomiting, and increasing headaches.
Despite more than 20 years of research on the causes and treatment of the disease, the prognosis of glioblastoma hasn't changed much.
"In the past decade, people have become increasingly conscious of glioblastoma with prominent political figures such as John McCain, Ted Kennedy, and Beau Biden succumbing to the disease and with President Biden’s Cancer Moonshot program," Priscilla Chan, an author of the study and a doctoral student in biomedical and biological sciences at the Keck School of Medicine of USC, told Interesting Engineering.
"This study raises awareness about the unmet need for effective treatments for recurrent glioblastoma and the poor prognosis of the disease in which patients, on average, succumb to the disease within 15 months after initial diagnosis."
Issey Takahashi
Using an AI algorithm
The tumor is typically detected through a brain scan, and then the patient undergoes a combination of surgery, radiation, and chemotherapy treatments. While most tumors significantly recede after the initial therapy, few patients experience long-lasting remission. In the majority of patients, the cancer is observed to return with resistance to chemotherapy and radiation.
Researchers believe that the reason why cancer returns is that a small number of cancer stem cells, which can multiply and spread very quickly, are left behind after the treatment combination.
To detect the perfect "lock-and-key" fit, the research team used an AI algorithm and observed how different molecules bind to clock proteins. They eventually identified one particularly promising molecule: SHP656.
Using glioblastoma stem cells collected from patients, the researchers demonstrated that SHP656 inhibited the growth of cancer stem cells but did not have a negative effect on normal stem cells.
"What makes this drug special is that when tested in the lab in different cell lines from patients with glioblastoma, it specifically causes cell death in glioblastoma stem cells but does not affect normal, healthy, non-cancerous cells. The drug has been tested in Phase I clinical trials in humans and has been found to be well tolerated and safe," added Chan.
SHP656 for treating many cancer types
SHP656 and other clock protein-targeting medicines show promise for not only treating glioblastoma but also for the treatment of various cancers. Kay and his team are also studying their utility in colorectal cancer, liver cancer, and acute myeloid leukemia.
"SHP656 specifically binds to a protein known as Cryptochrome 2, or CRY2, and prevents its degradation. CRY2 negatively regulates two core circadian clock proteins known as BMAL1 and CLOCK. We can shut down BMAL1 and CLOCK’s cellular functions by keeping CRY2 levels stable in the cell and in the lab that we showed that this led to the death of glioblastoma stem cells," Chan told IE.
"We believe these clock proteins may be involved in the growth of other cancers, so this gives us hope that we can develop this drug not only for glioblastoma treatment but also for other cancers as well."
The study was published in the peer-reviewed scientific journal Proceedings of the National Academy of Sciences of the United States of America.
Abstract:
The mammalian cryptochrome isoforms, CRY1 and CRY2, are core circadian clock regulators that work redundantly. Recent studies revealed distinct roles of these closely related homologs in clock output pathways. Isoform-selective control of CRY1 and CRY2 is critical for further understanding their redundant and distinct roles. KL001 was the first identified small-molecule CRY modulator that activates both CRY1 and CRY2. SHP656 is an orally available KL001 derivative and has shown efficacy in blood glucose control and inhibition of glioblastoma stem cell (GSC) growth in animal models. However, CRY isoform selectivity of SHP656 was uncharacterized, limiting understanding of the roles of CRY1 and CRY2. Here, we report the elucidation of CRY2 selectivity of SHP656. SHP656 lengthened cellular circadian period in a CRY2-dependent manner and selectively interacted with CRY2. By determining the X-ray crystal structure of CRY2 in complex with SHP656 and performing molecular dynamics simulations, we elucidated compound interaction mechanisms. SHP656 binding was compatible with the intrinsic CRY2 gatekeeper W417 “in” orientation and also a close “further in” conformation. Perturbation of W417 interaction with the lid loop resulted in a reduced effect of SHP656 on CRY2, supporting an important role of gatekeeper orientation in isoform selectivity. We also identified the R form of SHP656 (called SHP1703) as the active isomer. Treatment with SHP1703 effectively reduced GSC viability. Our results suggest a direct role of CRY2 in glioblastoma antitumorigenesis and provide a rationale for the selective modulation of CRY isoforms in the therapeutic treatment of glioblastoma and other circadian clock-related diseases.
