In a first-of-its-kind study, City of Hope scientists have measured changes in the flow of molecules through tiny blood vessels in the brain during treatment of brain tumors with neural stem cells. The work could help physicians time cancer treatment to be most effective.

Enhanced imaging lets researchers measure how permeable the blood brain barrier is in brain tumor patients. (Courtesy of Beth Chen)

Bihong Beth Chen, M.D., Ph.D., clinical assistant professor of radiology, presented early findings from the study at the Radiological Society of North America’s annual meeting on Dec. 1, 2011.

The study used an advanced imaging technique called Dynamic Contrast Enhanced Magnetic Resonance Imaging, or DCE-MRI, to see changes in brain tissue and blood vessels during an experimental brain cancer treatment using neural stem cells. These MRI brain scans showed researchers how receptive brain tissue was to absorbing cancer-killing therapy in the days after brain surgery.

The research is part of a City of Hope clinical trial led by Jana Portnow, M.D., assistant professor of medical oncology. It is the first study in humans to test the safety of using modified neural stem cells for the treatment of lethal forms of brain cancer, including glioblastoma.

The clinical trial is based on the research of Karen Aboody, M.D., associate professor of neurosciences and neurosurgery, who discovered the natural ability of neural stem cells to seek out and target brain tumor cells. Aboody’s team is harnessing these stem cells as carriers of therapeutic agents that focus chemotherapy directly at tumor sites, sparing the rest of the body from related toxic side effects.

In the current clinical trial, Behnam Badie, M.D., chief of the Division of Neurosurgery and lead neurosurgeon on the study, injects the neural stem cells into the brain when he performs a biopsy or surgery to remove the tumor. The researchers believe the stem cells then travel to the remaining tumor cells in the brain. Four days after surgery, Portnow gives the patient a compound called 5-fluorocytosine, or 5-FC. The 5-FC speeds through the bloodstream, but when it gets to the brain, the neural stem cells — now clustered around cancer cells — convert it to 5-fluorouracil, or 5-FU, which is an active chemotherapy drug that kills the cancer cells.

This is where the advanced imaging comes in.

Beth Chen, seated, studies brain images. (Photo by Walter Urie)

Before the 5-FC can get into the brain, it must cross the so-called “blood-brain barrier.” This barrier keeps potentially dangerous chemicals and germs from getting into brain tissue. Tiny blood vessels called capillaries in the brain act as gatekeepers; miniscule holes in the capillary walls expand to allow nutrients to flow from the blood into the brain, or they contract to prevent entry into the brain.

The blood-brain barrier can open a bit or tighten, and researchers wanted to see whether surgery and injection of the neural stem cells would affect the barrier. So they used the DCE-MRI to see how a special dye flowed from capillaries into the brain.

Chen and her colleagues found that the blood-brain barrier opened up within a day of the surgery and was most open after about five days.

“This is the best time to give the 5-FC so the concentration of the drug is highest and most effective at the tumor site,” Chen said. While more study is needed, she hopes the findings will help guide future drug dosing for brain cancer, so patients get the most out of their treatment.

While the imaging technique has shown promising results in the current clinical trial, it also may be useful for monitoring treatment of other types of cancer outside the brain, as well, according to Chen.

“We are working with advanced imaging techniques to improve our clinical protocols,” Chen said. “It is encouraging to see the imaging technique working for this trial.

“I feel fortunate to be part of the brain cancer team.”

The study was funded by the California Institute for Regenerative Medicine and the National Cancer Institute.