One of the main obstacles to treating brain tumors is finding a drug that can actually reach the cancer cells it is meant to fight. Now a new clinical trial will help City of Hope researchers measure just how well chemotherapy makes its way into the brain. The blood-brain barrier acts as a sieve to keep large, potentially toxic molecules out of the brain, explained Jana Portnow, M.D., assistant professor in the Department of Medical Oncology & Therapeutics Research and section chief of medical neuro-oncology. Unfortunately, that barrier also can keep critical drugs from reaching tumors in the brain.
 Microdialysis catheters similar to this one will help researchers understand how well chemotherapy crosses the blood-brain barrier. (Photo by Kaminsky Productions) |
Portnow is using funds from the Phase One Foundation to further her studies of intracerebral microdialysis as a technique to measure levels of anticancer drugs in the brain.
With intracerebral microdialysis, physicians implant a very thin catheter in the brain at the same time as they resect a patient’s tumor. The catheter has a semi-permeable membrane, which allows physicians to regularly sample brain fluid after a patient receives a dose of chemotherapy. Physicians test the fluid to identify how much of a chemotherapy drug is circulating in the brain.
Portnow recently received regulatory approval to use a new version of the catheter designed to measure levels of even larger molecules.
Her new phase I clinical trial will use the microdialysis technique to measure levels of cytokines and other proteins in the brain to see how they change in response to treatment with temsirolimus.
Temsirolimus inhibits the mammalian target of rapamycin (mTOR), which is part of a complex signaling pathway in tumor cells. Researchers believe temsirolimus can interfere with tumor cells’ growth and ability to nourish themselves.
Temsirolimus was approved in 2007 for the treatment of kidney cancer. Researchers also have studied it as a treatment for brain tumors, but it has demonstrated only a modest effect so far.
The clinical trial will indirectly test whether enough temsirolimus actually makes it through the blood-brain barrier to inhibit mTOR in brain tumor cells by measuring changes in cytokine levels in the brain in response to treatment with temsirolimus.
“We don’t know if it’s just not making it to tumor in the brain in high enough concentrations, or it does make it there and is just not as effective as it is against kidney cancer tumors,” said Portnow.
“As a neuro-oncologist, I think it is important to understand not only whether a chemotherapy agent can cross the blood-brain barrier, but also whether it gets into the brain in sufficient amounts to do what it is supposed to do. With this knowledge we can better select appropriate new agents for testing in brain tumor clinical trials,” she added.
Funding for the work comes from a larger Phase One Foundation grant to City of Hope. That $500,000 grant supports several researchers conducting early clinical trials into new therapies for metastatic disease that resists treatment. Portnow and other Phase One-funded researchers may be eligible for a second year of funding, as well.
Said Portnow: “The generosity of the Phase One Foundation enables me to continue my research into developing effective new treatments for brain tumors.”