Vitamin B12-like drug shows promise in preclinical glioma study
Data suggest experimental treatment may work along with chemotherapy
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An experimental therapy designed to mimic vitamin B12 and deliver a toxic molecule to tumor cells showed promise as a potential treatment for an aggressive form of glioma in a preclinical study.
Data suggest that the investigational treatment, NO-Cbl, may act in synergy with currently available chemotherapy treatments.
The study, “Selective blood–brain barrier penetration and tumor targeting of nitrosylcobalamin in glioblastoma: Pharmacokinetics, tissue distribution, and synergistic activity with trail and temozolomide,” was published in Oncoscience.
In a press release, the journal said the therapy “may represent a novel platform for improving therapeutic delivery and overcoming treatment resistance in one of the most challenging cancers in neuro-oncology.”
Glioblastoma multiforme (GBM) is one of the most aggressive and hard-to-treat forms of glioma. Part of the reason it’s difficult to treat is that it grows in the brain, and it’s difficult to get medications from the bloodstream into the brain. The blood-brain barrier (BBB) normally helps prevent toxins in the blood from entering the brain, but it also blocks many medications.
Vitamin B12 (also known as cobalamin) is a nutrient that cells require for a range of biochemical processes, particularly for making new DNA. Since cancer cells, by definition, rapidly copy their DNA and divide to make new cells, they tend to express high levels of the receptor that takes up vitamin B12.
Using cancer cells’ affinity for B12
NO-Cbl aims to exploit cancer cells’ reliance on vitamin B12. Essentially, NO-Cbl contains an analog of the vitamin that’s attached to a cell-killing molecule known as nitric oxide. The idea is that the vitamin will bind to receptors on cancer cells, and, in doing so, deliver the toxic molecule that kills the cell. Like naturally occurring vitamin B12, NO-Cbl can cross the BBB, moving into the brain where GBM tumors reside.
For their study, the researchers first conducted a series of tests in which they exposed different types of cancer cells to NO-Cbl. They found that blood cancer cells were most sensitive to the experimental therapy. GBM cells were a bit less sensitive than blood cancer cells, but were nonetheless much more sensitive than other cancer types, like breast and lung cancer.
The team then tracked the movement of NO-Cbl through the bodies of rats bearing GBM tumors in their brains. These experiments demonstrated that NO-Cbl could cross the BBB and accumulate near tumors, as expected. The researchers noted that NO-Cbl’s movements contrasted with those of typical chemotherapies, which usually accumulate in the bloodstream, with relatively little treatment getting through the BBB into the brain.
In a final set of experiments, the researchers treated GBM cell lines with NO-Cbl, either alone or in combination with the approved chemotherapy temozolomide (sold as Temodar and generics). On their own, both NO-Cbl and temozolomide had relatively modest success at killing cancer cells and slowing their growth. But when the two therapies were given in combination, they showed much greater potency.
Similar results were obtained in tests using NO-Cbl in combination with TRAIL (tumor necrosis factor-related apoptosis inducing ligand), a naturally occurring signaling molecule that can trigger cell death and has been explored as a potential anticancer therapy.
“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 scientists concluded. They emphasized that this was an early study done in lab models, noting that much more work is needed to explore the safety and efficacy of NO-Cbl before it can be tested in people.
