Targeting Brain Cancer, From Within and Without

by Elizabeth Norton Lasley

March 31, 2011

The brain tumor known as glioblastoma multiforme is among the deadliest of cancers. Even with the best available treatment, including surgery, radiation, and chemotherapy, most newly diagnosed patients survive for an average of only 14 months. Two new approaches may prolong life and avoid side effects--by coming at the brain tumors from opposite directions. One bombards the tumor with low doses of electromagnetic field through a soft helmet placed on the patient’s scalp, while the other delivers a lethal dose of chemotherapy straight into the cancerous cell.

Portable therapy

People who had tumor-treating field (TTField) therapy lived as long and reported better quality of life than those undergoing standard chemotherapy, according to the results of a clinical trial presented at the annual meeting of the American Society of Clinical Oncology in June 2010. And the subgroup of patients who used the device exactly as recommended in the trial protocol tended to have longer survival times compared with patients on the standard chemotherapy regimens, according to data presented at the annual meeting of the Society for Neuro-Oncology in November 2010.  TTField therapy delivers pulses of low-intensity, intermediate frequency electric fields that can penetrate the brain through the scalp. 

In the clinical trial, which involved 237 people already ill with recurrent glioblastoma, those using the technology had a median survival time of 6.6 months, compared to 6.0 months with chemotherapy alone. Of the 185 patients in the "fully compliant" subgroup, patients using the device had a median survival time of 7.8 months, compared to 6.1 months with chemotherapy alone. Their one-year survival rate was also higher—35 percent of people in the TTField-protocol-compliant subgroup versus 20 percent of those undergoing protocol chemotherapy. The treatment was also particularly effective in younger people.

The technique was pioneered by Yoram Palti of Technion-Israel Institute of Technology in Haifa, Israel. Patients carry a current-making device weighing about 6 pounds hooked up to a set of electrodes attached to the scalp. Exactly how the current destroys tumor cells is incompletely understood, but research suggests that it inhibits mitosis, the process by which cells divide, possibly by disrupting electrically charged components critical to the process.

“TTField is a totally new modality of treatment for cancer, and it certainly raised a few eyebrows at first,” says Eric Wong, principal investigator for the portion of the study conducted at Beth Israel Deaconess Medical Center in Boston. But Wong, along with scientists at 27 other centers in the U.S., Europe, and Israel, were sufficiently impressed with the research—especially an initial study in the June 12, 2007, Proceedings of the National Academy of Sciences—to participate in the clinical trial. “The results are encouraging,” Wong says. “At a minimum, the device works as well or better than traditional chemotherapy, without the need of other therapies.”

In addition to living longer, patients using TTField reported better quality of life, without the side effects of traditional chemotherapy for brain cancer—such as low blood counts that predispose patients to infection and bleeding. Some experienced irritation on the scalp from the electrodes, and users must shave their heads so that growing hair does not push the electrodes off and cause a mild shock (hair loss is not a typical side effect from the chemotherapy used for brain cancer).

Based on the clinical trial of patients with progressive glioblastoma, the Food and Drug Administration is actively considering approving the TTField technology. [UPDATE April 15, 2011: The FDA has approved the device (PDF)] A separate trial of patients with newly diagnosed glioblastoma continues (and seeks more volunteers); another trial showed impressive results using TTField therapy in non-small-cell lung cancer. The device is manufactured by NovoCure, whose U.S. operations are based in Portsmouth, N.H., and whose research center is in Haifa, Israel.

Wai-Kwan Alfred Yung, chairman of neuro-oncology at the University of Texas M.D. Anderson Cancer Center in Houston, finds the results of TTField impressive. He cautions, however, that questions remain regarding the science. “The therapy exposes the patient’s whole head to the electric fields,” he says. “Because the mode of action is not understood, it isn’t possible to say with certainty that the technique targets only the tumor, without affecting healthy brain tissue.”

Wong emphasizes the short survival time of patients with glioma. “We are dealing with a very sick group of patients without many options, so a treatment that can bring more time with better quality of life is very welcome,” he says.

Nanoengineering targets brain cancer cells

Another experimental therapy takes the opposite approach—designing a complex drug-delivery system based on a  clearly understood mechanism of action.

Researchers at Cedars-Sinai Medical Center, Los Angeles, have devised a method to deliver a tumor-specific inhibitor directly into a cancer cell while evading the cell’s defenses. Called a nanobioconjugate, the system is packaged in a naturally occurring substance that’s compatible with the brain and body. Injected intravenously, yet slipping through the intricate fence of blood vessels known as the blood-brain barrier, the treatment homes in on the tumor cell with a custom-devised or “monoclonal” antibody that binds to the transferrin receptor, which cancer cells produce abundantly. (Similar therapies for other cancers, targeting other tumor-specific receptors, are also in development).

Typically, molecules entering a cell through this receptor are wrapped in a series of membrane pockets known as endosomes, and then are recycled into products the cell can use or else are destroyed. To circumvent this process, the researchers added an escape device, a peptide that’s activated by the increasing acidity of the endosome chain. The conjugate then bursts out of the endosome and into the fluid inside the tumor cell, where the treatment can do its work.

The actual tumor inhibitor—the payload, so to speak—is “an antisense oligonucleotide,” a piece of DNA with a code exactly opposite that needed for a complex protein, laminin 411, which the tumor uses to build its network of blood vessels. By blocking the production of this protein, the treatment effectively starves the tumor without affecting normal brain cells, which do not produce new blood vessels and don’t contain laminin 411.

According to study author Julia Ljubimova at Cedars-Sinai Medical Center, Los Angeles, nanomedicines allow for the safe delivery of tumor-specific inhibitors or chemotherapy at a dose powerful enough to destroy the tumor without causing side effects. “You couldn’t give that many pills, for example, without major organ shutdown," she says.  

The nanobioconjugate devised by Ljubimova and colleagues showed dramatic results, eradicating cultured cancer cells and reducing, even eliminating tumors in mice implanted with human glioma cells. The study appeared in the Nov. 9, 2010, Proceedings of the National Academy of Sciences. The researchers are now studying the treatment’s safety in primates, after which they will apply for a clinical trial in humans. A similar design, also tested in mice, worked equally well on two different types of treatment-resistant breast cancer, as reported in the Feb. 15 Cancer Research.

Regarding the multi-step approach, Ljubimova says, “It was difficult to think through, but once we had the design in place, producing the delivery system was comparatively easy.”

J. Henry Kopecek, head of the Biomedical Polymers Laboratory at the University of Utah, whose lab has used nanomedicines against human ovarian and prostate cancer cells, commends the study. “To get the conjugate through the blood-brain barrier, into the cancer cell, and out of the endosome so the medication can do its work, is a great achievement.”