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Not Just Poisoning Cells: Brain Tumor Assault Has Many Fronts

BrainWaves

Spring/Summer 2002
Volume 15, Number 1

If it weren't for the brain tissue adjacent to a tumor, patients having surgery for primary brain cancers could be more optimistic. Yet the tissue surrounding tumor cavities is laced with neoplastic cells that defy removal: They're hard to reach, and they turn on chemo-resistant genes, all within the brain's immune-puny environment. Many patients survive less than a year.

John Laterra, Henry Brem look over a protein blot.
John Laterra, Henry Brem look
over a protein blot.

But Hopkins' clinician-scientists are becoming confident of a brain cancer turnaround from a scientific assault on several fronts. "We're finding ways to target the brain directly," says Neurosurgeon in Chief Henry Brem, M.D., "because we want to minimize side effects of such powerful treatments."

Basically, the scientists aim to kill residual tumor by raising the brain's immune response while simultaneously using selective chemotherapy to poison cells. Or they'll pretreat patients with agents that cripple cancer cells' resistance to drugs and then bring on the chemotherapy.

The assault hinges on improved drug delivery, long a stumbling block to therapy. Researchers here are trying stem and other engineered cells, microchips, dissolvable polymer discs and microspheres to reach tumors directly and ferry in potent therapies.

The therapeutic "workhorse" in many of the approaches is the Gliadel wafer, a dime-size polymer disc that Brem co-developed a decade ago. Placed in the brain after tumor removal, the thin wafers release a chemotherapeutic agent-BCNU-into adjacent tissues as the wafer disintegrates. Its 4 percent BCNU dose has lengthened patients' lives. But tests in Brem's lab suggest higher doses may be better. In recent clinical trials, neurosurgeon Alessandro Olivi, M.D., found malignant glioma patients tolerate doses five times higher. Efficacy trials are under way. And trials of the wafers with alternate agents, such as 5-FU and taxol, are also in the offing, as is a study of Col-3, an anti-angiogenesis drug neurologist John Laterra, M.D., Ph.D., and Brem have developed.

Recently, Hopkins researchers joined with MIT bioengineers to begin testing a centimeter-square, solid-state microchip that's implantable in the brain. The chip houses reservoirs of anti-cancer agents-single drugs or multiples that clinicians can release with remote controls as needed.

Since any drug is useless if tumors become resistant, another set of trials examines a way to inhibit an enzyme that makes it happen. Early tests suggest pretreatment with 06-benzylguanine can make cancer cells wither under a follow-up schedule of BCNU.

But the studies that cause researchers' sharpest intake of breath are still in animal testing. They're approaches that could realize a holy grail of brain-tumor treatment: the ability to destroy lingering tumor while conferring lasting immunity against it. The work centers on upping brain levels of cytokines, small proteins that stimulate an immune response.

In one study, Brem's team injected minute, gel-based spheres laden with a cytokine into rodents' brain tumors. Close to 90 percent rejected the tumors and survived. And more than a third of the animals survived when challenged with a lethal dose of malignant cells-a good sign there's immune memory.

But because most passive-delivery methods can't reach into tumors, Laterra is exploring cell-based tactics. He has, for example, injected endothelial cells engineered to secrete cytokines into rat models bearing tumors. The cells readily set up housekeeping in tumor tissue and extend the animals' survival. Laterra's also studying cytokine-engineered adult stem cells. They appear to migrate throughout the brain, settling wherever disease exists. "I'm very excited about these cells," says Laterra. "They've the potential to deliver what we want, where needed. And because they're destroyed along with the tumor in the immune response that follows, we shouldn't have to worry about what becomes of them."

For more information, call 410.955.4846.
The Web site listing clinical trials is http://www.nabtt.org.

 

 
 
 
 
 
 

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