It was a serendipitous finding. In a follow-up clinic for brain cancer patients who had undergone a procedure known as laser ablation — in which a minimally invasive probe is used to heat and kill a tumor — Dr. David Tran and colleagues repeatedly noted a “new ring of enhancement” around the tumor appearing on MRI soon after the procedure.
To Tran, now chief of neuro-oncology in the UF College of Medicine, and colleagues at Washington University School of Medicine in St. Louis, the “enhancement” could only mean one thing: Contrast material given to patients for the purposes of MRI scanning was leaking into the brain tissue surrounding the tumor. And that, they postulated, could only happen if there was disruption of the blood-brain barrier.
The exciting, unexpected finding suddenly lent hope in the fight against glioblastoma, the most common and deadliest brain cancer in adults. If the blood-brain barrier, a natural barrier of tightly packed cells lining the wall of blood vessels inside the brain that serves to block out toxins, bacteria and viruses, could be disrupted, there could be a window of opportunity to deliver chemotherapy drugs that are normally rejected by the barrier.
A second observation by the team was equally if not more important. If the disruption of the barrier lasted only a few hours, it would not be all that significant. But the permeability appeared to last four to six weeks, enough time for impermeable chemotherapy drugs to become effective against the highly aggressive glioblastoma by gaining access to the tumor.
“We reason that if we can disrupt the barrier within that space — one inch around the tumor — to allow chemotherapy to get in during that time window, we’ll be able to kill those infiltrating microscopic cancer cells that the neurosurgeon could not remove and thus prevent them from coming back,” Tran says. “That is a significant part of the discovery.”
The research, published in February in the journal PLOS One, was carried out at Washington University by a team led by Tran, neurosurgery Professor Dr. Eric C. Leuthardt and Dr. Joshua Shimony, associate professor of neuroradiology. The paper has generated so much interest the team was invited to do a live AMA (Ask Me Anything) on Reddit’s science page.
Now, the team is pushing ahead with two ongoing clinical trials being run at UF and Washington University. Early results suggest that a greater number of patients who receive the chemotherapy drug doxorubicin (which has limited permeability to the blood-brain barrier) while the barrier is disrupted appear to survive longer before a tumor comes back than those who receive it after the barrier has resealed. While further data is needed to confirm the preliminary findings in the trial of 40 patients, data thus far is encouraging, Tran says.
In a second ongoing trial, the team is using laser ablation to improve immunotherapy, a treatment that stimulates a patient’s own immune system to attack cancer cells. Typically, a patient’s immune system will kick in following laser ablation and “clean up” the dead tissues, creating inflammation and an environment akin to that resulting from a vaccine, Tran says. The team will use ablation to activate the immune system first and then give a drug that prevents the cancer from “turning it off,” he says. The result, Tran hopes, is a therapeutic synergy that will help keep the disease from coming back.
The research is being funded by the National Institutes of Health, the Foundation for Barnes-Jewish Hospital’s Cancer Frontier Fund, the Alvin J. Siteman Cancer Center in St. Louis and Merck.
Results from the trials are expected within a couple of years; if prolonged survival is confirmed, larger definitive trials would be needed.
“I think we’re making inroads,” Tran says. “We’re prolonging patients’ lives incrementally, but any amount of survival advantage is welcome in this field when there are very few options.”