A groundbreaking new compound is showing promise in the fight against glioblastoma, the most aggressive and lethal form of brain cancer in adults. SHP1705, developed through collaborative research, specifically targets circadian clock proteins that glioblastoma stem cells exploit to fuel their growth and survival, according to findings published in the journal Neuro-Oncology.
Glioblastoma remains notoriously resistant to conventional treatments including surgery, radiation, and chemotherapy, with tumors frequently recurring after initial treatment. The discovery that these cancer cells hijack circadian clock proteins—which regulate various biological rhythms within the body—has opened a new therapeutic avenue that SHP1705 is designed to exploit.
Mechanism of Action
SHP1705 functions as a CRY activator, enhancing the activity of cryptochrome (CRY) proteins within cells. The compound specifically targets a variant called CRY2, which researchers have found at reduced levels in glioblastoma cells.
"There is increasing evidence indicating that brain cancer stem cells utilize circadian clock proteins to fuel their growth," explained Steve A. Kay, a leading researcher in the study and professor at the Keck School of Medicine of USC. "By targeting these proteins, we can disrupt the replication process of these malignant cells."
By increasing CRY2 activity, SHP1705 effectively disrupts the circadian clock mechanisms in cancer cells while minimally affecting healthy brain tissue—a critical factor in developing treatments for brain cancers.
Promising Preclinical Results
In laboratory studies, SHP1705 demonstrated remarkable efficacy against glioblastoma stem cells, including those resistant to chemotherapy. The compound impaired the survival capabilities of these cancer cells across multiple cell lines.
Further mouse studies revealed dose-dependent benefits, with higher dosages of SHP1705 not only slowing tumor growth but also extending survival rates. Perhaps most significantly, the compound appeared to enhance the efficacy of radiation therapy by increasing cancer cell mortality following treatment.
Researchers also discovered potential synergistic effects when combining SHP1705 with another compound called SR29065, which targets a different aspect of the circadian clock. This combination showed improved results, suggesting a possible multi-pronged approach to treatment.
Clinical Progress
SHP1705 has become the first clock-targeting compound to complete a Phase 1 clinical trial. The study, conducted by Synchronicity Pharma—a biotech company co-founded by Kay—involved 54 healthy participants and confirmed the compound's safety profile.
Only minor side effects were reported during the trial, including headache and nausea, establishing SHP1705 as well-tolerated in humans. The compound's oral administration route presents a convenient treatment option for patients already undergoing intensive therapies.
Jeremy Rich from the University of North Carolina at Chapel Hill, who collaborated with Kay on developing SHP1705, emphasized the significance of these findings: "Current treatment protocols do not adequately address the presence of glioblastoma stem cells, which are believed to contribute significantly to cancer recurrence. SHP1705 could fill this critical gap in our treatment approach."
Future Directions
The research team is now preparing for a Phase 2 clinical trial, where SHP1705 will be evaluated in conjunction with standard treatments including surgery, chemotherapy, and radiation. This next phase will assess the compound's efficacy specifically in glioblastoma patients.
Beyond glioblastoma, investigators are exploring the broader implications of targeting circadian clock proteins, as these mechanisms may play roles in other types of tumor growth and immune suppression.
The development of SHP1705 represents a precision strategy in cancer treatment, moving away from broadly cytotoxic approaches toward more targeted therapies that exploit specific vulnerabilities in cancer cells.
For patients facing the devastating diagnosis of glioblastoma, which currently has a median survival of approximately 15 months with standard treatment, the development of SHP1705 offers a new ray of hope in what has long been one of oncology's most challenging battlegrounds.
