M. D. Anderson: Setting The Benchmark In Brain Tumor Treatme(2)

In mice, the treatment completely eradicated gliomas, a "response that has never been seen before," says Juan Fueyo, M.D., the researcher who developed the treatment. The mice were considered clinically cured of their brain tumors, and in examinations, researchers found only empty cavities and scar tissue where the tumors had once been.

To create the therapy, Fueyo and his research team focused on a protein that malfunctions in nearly all malignant gliomas as well as in many other solid tumors - retinoblastoma (Rb), which acts like a brake on cell division.

In normal cells, the Rb protein prevents a virus from replicating after it enters a cell. But adenoviruses, like the one that causes the common cold, counteract that defensive measure by expressing their own protein (E1A) to bind to Rb and stop it from functioning, allowing the virus to replicate, or reproduce.

Fueyo took advantage of the mutant Rb protein in cancer cells. He created a virus in which E1A does not function, which allows it to attack only cancer cells that are missing Rb. Since normal brain cells have normal Rb, the killing virus does not affect these non-cancerous brain cells.

"Cancer is devious, but this virus is equally tricky," says Lang, the neurosurgeon who will help conduct the trial with Charles Conrad, M.D., associate professor in the Department of Neuro-Oncology. Lang will insert a catheter into participants' brain tumors, inject Delta-24-RGD and wait two weeks to surgically remove the malignancy. The tumor will then be examined to see how much of it has been destroyed.

Fueyo and Lang are considering testing new variations of the viral treatment, if it proves safe in patients. One is to eliminate the need for a catheter by delivering the virus in mesenchymal stem cell, a specialized cell derived from the bone marrow that may be involved, among other functions, in repairing injured tissue or wounds. Collaborative research between Lang and Michael Andreeff, M.D., Ph.D., chair of the Department of Bone and Marrow Transplant, has found that because the tumor environment mimics a "never-healing wound," these mesenchymal stem cells preferentially home in to tumors wherever they exist, even if the tumor exists in the unique environment of the brain and the stem cells need to cross the blood-brain barrier. Lang and Fueyo believe the virus could be hidden as if in a Trojan horse inside the stem cells. Once in the tumor, it would break out from the stem cell and destroy the tumor. This strategy also may reduce any immune reaction that a naked virus might otherwise provoke.

"Thinking outside of the box may be the only way to defeat these tumors," says Fueyo.

Boosting immunity, evading the barrier
Novel approaches reach patients

Neurosurgeon and researcher Amy Heimberger, M.D., agrees. She is focusing on the power of immunity to help keep a brain tumor at bay, and so far, the phase II clinical trial she leads is significantly increasing the expected life span of enrolled patients.

Along with investigators at Duke University Medical Center, Heimberger designed a vaccine that alerts the immune system in the brain to the presence of just one type of protein that studs the outside of a glioma. In fact, the protein, epidermal growth factor variant III (EGFRvIII), is found on brain tumors, as well as on breast and non-small-cell lung cancers. Heimberger believes it drives gliomas to spread, explaining why they are unusually dangerously and invasive.

Patients at M. D. Anderson and at Duke whose brain tumors, once removed, show evidence of the protein are eligible for treatment with the vaccine, which contains a synthesized piece of the protein and a stimulator for the patient's dendritic cells that activate the immune system.

The research team examined the first 23 patients enrolled in the 44-patient trial, and found that it took the tumors significantly longer than is typical to come back. When the recurring tumors were removed, there was no longer any evidence of the EGFRvIII protein on the new glioma - an indication that the vaccine worked but that the tumor morphed to use a different pathway to grow again. Median survival among the treated patients also was significantly longer, at least 18 months. As of spring 2006, only three patients have died.

Heimberger says that if the vaccine continues to prove beneficial in future testing, it probably should be combined with chemotherapy treatment. New findings show the chemotherapy can change tumor cells so they are more susceptible to destruction by the immune system.

"This is exciting to us because people have been trying to use immunotherapy against gliomas for a long time," she says. "We need to find ways so that these therapies can work together synergistically." She adds that the vaccine could potentially be used for breast and lung cancers, and a trial has been opened at the University of Washington to test this hypothesis.

Other researchers are working to overcome a major hurdle in the use of chemotherapy drugs. Many that are effective for other cancers cannot cross the blood-brain barrier to treat brain cancers. A research team led by Waldemar Priebe, Ph.D., a professor in the Department of Experimental Therapeutics, has developed a unique approach to identify a new kind of chemotherapy that effectively penetrates the blood-brain barrier - and targets topoisomerase II, a key protein involved in the proliferation of malignant gliomas.

A multidisciplinary collaboration between Priebe, Conrad, and Timothy Madden, M.D., associate professor in the Department of Experiment Therapeutics, has led to a rapid translation to preclinical and clinical development of the drug, WP744 (also known as RTA744). A phase I, 30-patient clinical trial at M. D. Anderson, which is being led by Conrad, is in progress.

"This design of WP744 was based on doxorubicin, a widely used drug that is very potent and effective in a lot of solid tumors, but which always has been pumped out of the brain faster than it could accumulate in tumor tissue," Priebe says. "This new drug may represent a treatment not only for tumors that originate in the brain, but also for cancers that tend to metastasize to the brain."

Other novel strategies being investigated at the Brain Tumor Center include use of Temodar with Accutane (isotretinoin), the acne drug, which appears to downshift the ability of gliomas to spread through the brain, Conrad says.

"I think the most important part of the drug cocktail that we hope to eventually give to patients are agents that help block invasion," he says. "We have identified a number of targets and tactics that appear to be promising, and some of them may show up in the clinic in a few years. We have a real sense, and an optimism, that advances are coming."

The newest "old" tools
Optimizing what works - surgery and radiation

Just as researchers are developing new therapeutic agents, surgeons and radiation oncologists at the Brain Tumor Center are maximizing the tools that have long been used to treat brain tumors.

Surgery is a critical component of brain and spine tumor treatment. Neurosurgeons at the center perform more than 1,400 operations annually - one of the largest volume of tumor surgeries in the country. They believe that removing as much of a brain tumor as possible, while sparing precious tissue, will offer patients the greatest chance of a longer life.

In fact, M. D. Anderson surgeons published a landmark study in 2001 demonstrating that the extent of tumor removal is a critical success factor in treating glioblastoma. They found that patients who had 98 percent or more of their visible tumor removed showed the longest life span - including some who lived as long as eight years post-surgery.

Sawaya says their radical surgical approach differs from the majority of neurosurgeons who partially cut, or suction, tumors out of the brain in the belief that it is impossible to remove all of the tumor without harming the patient.

"In fact, the brain is amazing, because it is possible to remove a portion of it without affecting function," Sawaya says. "But you only can be successful if you are selective and specific in identifying what is essential and what is not, and the only long term glioblastoma brain tumor survivors are the ones that have had radical resections in the first place," he says.

Such intricate surgery, however, requires the most technologically advanced equipment available to help distinguish tumor tissue from normal brain matter. According to Sawaya, the Brain Tumor Center has such leading tools, including stereotactic image-guided surgery that uses computers to help surgeons navigate in the brain, a robotic microscope called the SurgiScope and a plethora of imaging tools, such as functional magnetic resonance (fMRI), to identify areas in the brain to avoid.

Sawaya adds that another advance is in store. Neurosurgeons at the Brain Tumor Center will soon operate in a technology-rich environment that is like few, if any other, in the world, he says. In spring 2006, the surgeons will begin to use the $9.2 million "BrainSUITE," which integrates the latest surgical and diagnostic tools in one operating room. Surgeons will be able to use three-dimensional images of the brain and MRI scanning during operations. A navigation system will track the movement of the surgeon's instruments.

"It's another great tool to use in our battle against brain tumors," says neurosurgeon Jeffrey Weinberg, M.D.

All of this technology is expected to help surgeons home in on the tumor while avoiding critical brain structures, thus reducing the kinds of neurological deficits that lead to impaired quality of life, says Sawaya. (责任编辑：泉水)

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M. D. Anderson: Setting The Benchmark In Brain Tumor Treatme(2)