New Compound SHP1705 Shows Promise in Targeting Glioblastoma via Circadian Clock Mechanisms

Recent research highlights the potential of a novel compound, SHP1705, in the treatment of glioblastoma, a highly aggressive form of brain cancer. This experimental drug targets circadian clock proteins that glioblastoma stem cells exploit for growth, thereby impairing the cancer cells' ability to thrive and proliferate. Published in the journal Neuro-Oncology, the study outlines the findings from a series of preclinical trials that demonstrate the efficacy and safety of SHP1705.

Glioblastoma is recognized as the most prevalent malignant brain tumor in adults, notoriously resistant to conventional treatments such as surgery, radiation, and chemotherapy. These tumors often recur, presenting significant challenges for healthcare providers. The discovery that glioblastoma cells can hijack circadian clock proteins, which regulate various biological rhythms within the body, offers a new avenue for therapeutic intervention. By disabling these proteins, researchers aim to slow down or stop tumor growth.

Steve A. Kay, a leading researcher in this study and a professor at the Keck School of Medicine of USC, noted that there is increasing evidence indicating that brain cancer stem cells utilize circadian clock proteins to fuel their growth. Targeting these proteins could disrupt the replication process of these malignant cells.

Kay, along with Jeremy Rich from the University of North Carolina at Chapel Hill, is at the forefront of a collaborative effort developing SHP1705. Through extensive biochemical and cellular studies, they have confirmed the compound's ability to neutralize glioblastoma stem cells effectively. Initial results from a phase 1 clinical trial conducted by Synchronicity Pharma, a biotech company co-founded by Kay, indicate that SHP1705 is well-tolerated in human subjects.

SHP1705 functions as a CRY activator, enhancing the activity of cryptochrome (CRY) proteins within cells. The compound specifically targets a variant of the CRY protein known as CRY2, which is found at reduced levels in glioblastoma cells. By increasing CRY2 activity, SHP1705 effectively disrupts the circadian clock mechanisms in these cancer cells while minimally affecting healthy brain cells.

In preclinical trials, SHP1705 was shown to impair the survival of glioblastoma stem cells, demonstrating effectiveness against both chemotherapy-sensitive and resistant cell lines. Further mouse studies revealed that a higher dosage of SHP1705 not only slowed tumor growth but also extended survival rates. Moreover, the compound appeared to enhance the efficacy of radiation therapy by increasing cancer cell mortality post-treatment.

In combination with another compound known as SR29065, which targets a different aspect of the circadian clock, SHP1705 showed improved results, suggesting potential synergistic effects that could enhance treatment outcomes.

The phase 1 clinical trial, involving 54 healthy participants, confirmed the safety profile of SHP1705, with only minor side effects reported, including headache and nausea. The next step involves a phase 2 clinical trial, where SHP1705 will be evaluated in conjunction with standard treatments like surgery, chemotherapy, and radiation. The compound's oral administration allows for a convenient treatment option for patients undergoing intensive therapies.

Current treatment protocols do not adequately address the presence of glioblastoma stem cells, which are believed to contribute significantly to cancer recurrence. The research team is optimistic that SHP1705 could fill this critical gap. Additionally, ongoing investigations are exploring the broader implications of targeting circadian clock proteins, as these proteins may also play roles in tumor growth and immune suppression.