Patients diagnosed with glioblastoma typically survive less than 15 months, even after surgery, radiation therapy and chemotherapy. A big part of the problem is the blood-brain barrier, a protective structure that keeps many drugs from ever reaching a tumor in the brain.
A study in the journal Oncoscience now describes a compound that appears to get through. In animal experiments, a modified form of vitamin B12 crossed the barrier and collected in glioblastoma tissue.
What the team tested
Joseph A. Bauer of Nitric Oxide Services, LLC and the Cleveland Clinic Foundation Taussig Cancer Center led the work as first and corresponding author. His team studied nitrosylcobalamin, or NO-Cbl, a version of B12 that releases nitric oxide.
They tried it three ways. They ran it against cancer cells in the NCI-60 human tumor cell line panel, measured how it moved through rats with glioblastoma tumors, and combined it with other treatments in human glioblastoma cell lines. Tumor cells from the central nervous system showed a moderate level of sensitivity, and the compound had antitumor activity across a wide range of cancer types.
After the compound was given systemically, it crossed the barrier and built up preferentially in the tumor tissue. Nitrate levels in the tumors stayed high for at least 24 hours after treatment, while levels in normal tissue fell faster. The authors read that as a sign the compound is retained in tumors and delivers nitric oxide to them directly.
Working alongside existing drugs
In U87 and D54 glioblastoma cells, pairing NO-Cbl with either TRAIL or temozolomide suppressed tumor growth far more than any of the treatments did alone. Further analysis found synergy across several dose ranges.
The paper also cites earlier research suggesting NO-Cbl can trigger cell death through caspase-8 activation, suppress NF-kB survival signaling and strengthen TRAIL receptor signaling. Together, the authors say, those effects could make glioblastoma cells more responsive to therapy, including tumors that have stopped responding to temozolomide.
“This pilot study demonstrates that NO-Cbl crosses the BBB, accumulates selectively in brain tumor tissue, and synergizes with established and experimental glioblastoma therapies,” the paper states.
The authors stress that this is a pilot translational study and that more work is needed before anyone considers clinical use. Next steps include orthotopic validation, tuning the dosing, tracking nitric oxide activity over longer periods, and testing the mechanism in other central nervous system tumor models. No treatment based on the work is available to patients.
