Try squeezing a watermelon through a chain-link fence. Sound difficult? That is how hard it can be for some chemotherapy drugs to reach the brain.
A network of microscopic pores dot the walls of tiny blood vessels that course through and feed the brain — and more often than not, big drug molecules in the blood cannot seep through these gaps to reach the diseased brain tissues they are meant to heal.
Called the blood-brain barrier, this “fence” between the circulatory system and central nervous system allows important nutrients to get to brain cells while protecting them from infectious invaders and toxic chemicals. Yet it also poses one of the biggest hurdles to physicians who treat brain cancer patients, because the blood-brain barrier blocks 98 percent of drugs from reaching tissues of the brain. Fortunately, though, physicians such as Jana Portnow, M.D., a medical oncologist at City of Hope, are helping to find ways around this obstacle.
“Compared to other types of cancers, it often takes longer to get new drugs into brain tumor clinical trials,” explains Portnow, assistant professor in medical oncology and therapeutics research. “One reason is that we first need to determine if a new chemotherapy agent can cross the blood-brain barrier and achieve therapeutic levels in the brain.”
Portnow’s research involves applying the technique of microdialysis to determine if new drugs can cross the blood-brain barrier. She is principal investigator on a clinical trial that tests whether a catheter threaded into the brain can detect and measure levels of chemotherapy drugs. If it works, it could be used to evaluate promising cancer-fighting drugs and may speed new therapies to brain cancer patients.
Slimmer than a piece of spaghetti and smaller than the typical needle neurosurgeons use to take brain biopsies, the soft, flexible catheter has a semi-permeable membrane at its tip and can accurately measure levels of various substances in the brain. Approved by the United States Food and Drug Administration for use in the brain, such catheters form part of the tool kit of neurosurgeons, who already use them to measure glucose and other substances in the brain tissue of head-trauma patients.
In her study, Portnow will assess how much of the drug temozolomide reaches brain tissue. Tomozolomide is an oral chemotherapy commonly used to treat brain tumors. Patients with primary brain tumors (gliomas) or brain metastases from other cancers may be eligible to participate.
Neurosurgeon Behnam Badie, M.D., director of the Brain Tumor Program and associate professor of tumor cell biology, collaborates with Portnow on the study. If Badie is able to resect a study patient’s brain tumor, he inserts the tiny catheter into the brain tissue surrounding the cavity left by the tumor. If the tumor is unresectable, he inserts the catheter directly into the tumor tissue. The catheter stays in place for about 48 hours while patients remain hospitalized.
After the surgery, patients receive a dose of temozolomide. At the same time, a compact pump gently pushes drops of artificial cerebrospinal fluid through the catheter. Interstitial fluid — the natural fluid that bathes cells — seeps back into the catheter and is collected to test how much temozolomide has reached the brain tissues.
As Portnow explains, “Once we show our microdialysis technique works — that we can detect levels in the brain of a drug that we already know crosses the blood-brain barrier — then we can apply this technique to screen new drugs for their ability to get into the brain.” Such a rapid process for evaluating drugs would likely speed such drugs to brain tumor patients. “Information gained from this study will help patients down the road,” she said.
The General Clinical Research Center at City of Hope sponsors the study, which is also made possible through Portnow’s K12 funding from the National Cancer Institute. The K12 grant, called the Paul Calabresi Award for Clinical Oncology, supports clinical investigators at City of Hope who work with basic scientists to perform translational research to fight cancer.