Nitric oxide kills cancer cells. Getting it into a brain tumor is the hard part, and a team at the Cleveland Clinic Foundation Taussig Cancer Center says it found a way in: hide it inside vitamin B12.
The work, published in Oncoscience, was led by Dr. Joseph A. Bauer of the Taussig center and Nitric Oxide Services, LLC. Bauer is the first and corresponding author. The compound is nitrosylcobalamin, or NO-Cbl, a form of B12 engineered to release nitric oxide.
A barrier that stops most drugs
Glioblastoma patients usually survive less than 15 months, even with surgery, radiation and chemotherapy. One fundamental reason is the blood-brain barrier, which blocks most drugs from reaching the brain at therapeutic concentrations.
The barrier exists for a good reason. It protects the brain from toxins, pathogens and circulating molecules that could disrupt neural function. The side effect is that most chemotherapy agents and many targeted cancer drugs cannot cross it in amounts large enough to kill a tumor.
According to the American Cancer Society, glioblastoma multiforme kills approximately 14,000 Americans a year. The standard of care is the Stupp Protocol, which combines surgery, radiation and temozolomide chemotherapy. It was established in 2005 and remains the backbone of treatment. Progress since then has been counted in weeks and months, not years.
What the researchers found
The brain takes in cobalamin through specific transport receptors. By attaching a nitric oxide-releasing group to B12, the team built a compound that those same transport systems can carry across. Tumors, with their heavy metabolic demands and altered uptake, then accumulate more of it than the healthy tissue around them.
The team used cell lines from the NCI-60 human tumor panel, animal models of glioblastoma and pharmacokinetic distribution studies. In the animals, NO-Cbl crossed the barrier after systemic administration and collected preferentially in glioblastoma tissue compared with normal brain tissue. Nitrate levels in tumor tissue stayed elevated for at least 24 hours after treatment. In normal tissue they dropped more quickly.
When NO-Cbl was combined with TRAIL, a tumor-killing protein, or with temozolomide, tumor cell growth was suppressed significantly more than with either therapy alone.
“By combining blood-brain barrier penetration, selective tumor targeting, and enhanced activity alongside existing therapies, NO-Cbl may offer a new way to improve drug delivery and combat treatment resistance in one of the most challenging cancers in neuro-oncology,” the researchers wrote.
Early stage
The study is pre-clinical. It used animal models and cell lines, and the authors were explicit that more research is needed before any clinical use. Animal models of glioblastoma reproduce some but not all features of human tumors, and the dense stromal environment of the human disease is particularly hard to model. The compound has not entered Phase I human safety trials.
The compound is also not the B12 sold as a supplement. Standard supplements are not designed to deliver nitric oxide or target tumors, and no product has been approved by the FDA for brain cancer on this basis.
Next would come further animal testing, including the toxicology studies required before human trials. If those go well, an investigational new drug application to the FDA would follow, ahead of Phase I trials. MedicalDaily puts that pathway at typically 3 to 7 years from the current results to first-in-human trials.
Sources
- Scientists Used Vitamin B12 to Sneak a Cancer-Killer into the Brain, and It Worked on Tumors in Animal Studies
- This new vitamin B12 therapy shows promise against deadly brain cancer: Study
