Brain tumor specialists at The University of Texas M. D. Anderson Cancer Center are poised on the brink of a new era.
The molecular revolution that has led to improvements in treating other cancer types is well under way at the institute's Brain Tumor Center. For the first time in decades, new therapies are bringing hope to patients and physicians. And at long last, glioblastoma, the most common and deadly of brain tumors, is finally giving up some secrets.
Encouraged by the finding that a new chemotherapy drug works best in patients who have no expression of a specific genetic alteration, researchers at the Brain Tumor Center are leading the U.S. arm of a worldwide study that aims to characterize as many as 20,000 genes and proteins that may play a role in brain tumor development.
They have other reasons to be optimistic. A vaccine that tricks the immune system into attacking a protein found on glioblastoma cells is showing promise in patients treated at the Brain Tumor Center. A clinical trial is soon to open on a virus designed to spread rapidly through the extended fingers of a brain tumor, killing it while leaving normal tissue alone. Another trial is studying a chemotherapy drug that can seep through the brain-blood barrier and latch on to tumor cells. All of these experimental approaches were developed at M. D. Anderson. Some have the backing of the National Cancer Institute as well as the interest of pharmaceutical companies.
Traditional brain tumor therapies also are being refined at the Brain Tumor Center with this next-generation technology that will offer safer, more precise treatment. A proton synchrotron particle accelerator will be online in 2006 to offer some brain tumor patients the most precise radiation therapy available, as will a new suite of neurosurgical devices featuring real-time imaging that surgeons can use to navigate inside the brain.
While the co-directors of the Brain Tumor Center are energized about the future, they also are realistic. The finest surgery, medical and radiation treatments are not enough, they say. Next-generation drugs must be developed to change the forecast for most glioblastoma patients. The road to developing a fleet of agents designed to disarm the numerous pathways brain tumors use to thrive will surely be a bumpy one.
"There will be no magic bullet to treat brain cancer," says Raymond Sawaya, M. D., professor and chair of the Department of Neurosurgery. "The answer is not going to come from one approach. We have to test and prefect many different avenues for treatment, and hit the right combination of multiple drugs and therapies that works best for each individual patient."
"We are just now on the cusp of understanding much more about the molecular biology of the disease," says W. K. Alfred Yung, M.D., professor and chair of the Department of Neuro-oncology. "What we are learning right now can only improve our ability to treat each tumor, and each patient."
Reading the molecular signature
Hunt for genes springs from chemotherapy success
For the first time, there is a chink in the armor of one of the most deadly human tumors. The chemotherapy drug Temodar (temozolomide), first tested by M. D. Anderson researchers in recurrent glioblastoma and approved for use in those tumors last year, bumps up the life span in some patients by a number of months. A few who participated in early clinical testing of the drug are alive years beyond what was expected.
Researchers know that resistance to Temodar occurs in many patients. They also now understand that patients who initially respond to it have a specific DNA repair gene (0-6-methylguanine-DNA methyltransferase or MGMT) that remains silent during treatment. Temodar does not help patients with an active, efficient MGMT gene - their cancer cells are being mended as fast as the drug can injure them.
A test may soon be available to pinpoint patients best served by Temodar. This first baby step toward individualized therapy for brain tumors constitutes a huge moment in the study and treatment of aggressive brain tumors.
Uncovering this one secret in the molecular doings of glioblastoma has bolstered the spirits of brain tumor researchers and clinicians worldwide, says neuro-oncologist Mark Gilbert, M.D. "Temodar is the first new brain tumor treatment approved for use in the last 20 years, and the fact that it works better in some patients has energized the field."
Researchers from the United States, Europe and Canada are now collaborating on the largest brain tumor clinical trial ever undertaken, he says. They have launched a phase III test of Temodar, testing 840 glioblastoma patients to see whether increasing doses of the drug will overcome the repair gene problem.
"This kind of collaboration is exciting, and it is unprecedented, not only in brain tumor research but in cancer research across the board," says Gilbert, the study's principal investigator. "I think the entire cancer community is recognizing that the whole is greater than the sum of the parts."
The study, which has recently begun enrolling patients in some sites, also aims to collect uniform tumor samples from every participant, another first, Gilbert says. "In the past, institutions have differed in the way they collect such samples, which means these samples are hard to compare to each other," he says. "For the first time, all centers participating in this trial will be collecting them in a uniform way so that we can study all samples and put the information we find into a comprehensive database."
The tissue will be examined for its MGMT status, which will then be correlated with outcome for each patient. These tissue samples will be further studied to determine the genes and proteins that are switched on at the time the biopsy was taken. Such information will help identify the molecular pathways that cancer cells use to override normal growth controls.
In the United States, all samples will be sent to Ken Aldape, M.D., at the Brain Tumor Center at M. D. Anderson. "Normally, molecular profiling is done on samples of convenience - on whatever you can find in your laboratory freezer - and so that kind of analysis has not told us that much," says Aldape, lead U.S. pathologist for the trial. "This is an unprecedented effort to understand precisely what is going on in brain tumors."
Gilbert says that up to 20,000 genes and proteins can be characterized through this screening process, and the results will be compared to the dozen different pathways known to be active in many cancers. Among the more common genetic alterations seen in malignant brain tumors are: the p53 tumor suppressor gene, EGFR genes that control cell growth, PDGF and VEGF genes involved in cell growth and angiogenesis and the MMAC/PTEN tumor suppressor gene.
"In the last ten years, we have learned an amazing amount about all the different pathways glioma cells use," says neurosurgeon Frederick Lang, M.D. "These tumor cells are very smart, they mutate rapidly, they have a lot of fallback pathways and we haven't found an Achilles' heel yet."
Still, Aldape says that this gene screening may identify new pathways. With the molecular profiles in hand, researchers may then begin to rationally analyze targeted therapies that have a chance of working on malignant brain tumors, including those for which Temodar has not worked. Agents are approved or are being developed that work in each of these pathways, Gilbert says.
"The dream in the field is that the molecular profile of the patient's tumor will drive the treatment and that we can quickly test a number of different combined drugs against the particular tumor, which is the essence of individualized treatment," he says.
Researchers at the Brain Tumor Center are the first to point out that use of a single targeted therapy has not worked well so far to fix errant pathways. A trial of a gene therapy vector to replace the p53 gene missing in most brain tumors failed, as did an attempt to use a drug that blocks over-expression of EGFR, which is amplified in about 60 percent of glioblastomas. Single agent tests of other targeted therapies, such as platelet-derived growth factor (PDGF) and Ras inhibitors, have not worked. Gleevec, which has revolutionized the treatment of chronic myelogenous leukemia, was first tested in brain tumors to little effect.
Gilbert predicts that years will pass before testing of combined agents is routine. Drug testing guidelines are not yet flexible enough to allow clinicians to test approved agents with experimental therapies, he says, and issues will pop up as to who owns a winning drug combination. Still, Gilbert adds, "It is great to have the world working together."
Novel viruses and Trojan horses
NCI endorses testing a smart virus
A different and completely novel approach - a "viral smart bomb" - that was developed at the Brain Tumor Center is designed to go after cancers cells and spare normal cells based on differences in the molecular makeup of cancer cells and normal cells.
It is considered so promising that the National Cancer Institute is producing a drug-grade version of the virus, and a clinical trial is slated to begin in the fall of 2006.
The therapy, known as Delta-24-RGD, is a new-generation "replication-competent oncolytic" adenovirus therapy. It is a therapeutic virus that spreads, wavelike, throughout a tumor, infecting and killing cancer cells along the infiltrative fingers of brain tumors, but that does not affect normal cells.
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.
Radiation therapy also has been part of the standard of care in brain tumors, but such treatment is especially tricky in the brain, given that tumors are embedded within functional folds of tissue. However, radiation oncologists at M. D. Anderson who specialize in treatment of brain tumors have improved imaging to the point that they can "conform" the beam of therapeutic radiation to match the tumor, says Shiao Woo, M.D., a professor in the Department of Radiation Oncology.
"Instead of treating a large area of brain, we can now use multiple beams to shape radiation around the tumor," says Woo. "This allows us to avoid critical structures and much of the surrounding brain, and that minimizes the treatment's impact on brain functions."
Additionally, a freestanding Proton Therapy Center will open at M. D. Anderson in spring 2006, Offering the most precise form of radiation treatment available. Some brain tumors may be candidates for treatment by the device, which uses a highly focused, pencil-thin beam that stops at the tumor, instead of passing through it as does standard radiation treatment does.
"For brain tumors that are potentially curable, this is the ultimate radiation technology," says James Cox, M.D., a professor and head of the Division of Radiation Oncology.
Moving on with life
Working to reduce post-treatment complications
At the Brain Tumor Center, the focus is on the whole person - not just the tumor.
Brain tumor patients often experience cognitive and functional difficulties as a consequence of traditional therapies and the tumor's proximity to vital functions controlled by that part of the brain. While the removal of a tumor may result in some impairment, chemotherapy and radiation treatments also play a role in hindering a person's ability to think and perform daily activities.
These therapies preferentially affect the outer lining of the nerve fibers of the brain, which serves to insulate and facilitate the transmission of nerve impulses. Patients often become slow and unmotivated. They may have trouble concentrating and remembering, become forgetful and distracted and experience personality changes and mood swings. These effects may be long-lasting and progressive.
M. D. Anderson's neuropsychologists were the pioneers - and are now leaders - in studying the long-term effects of brain cancer in terms of mood and ability to function. "Brain cancer is a disabling condition that causes impairment of real life functions, including poor memory, problems with communication, socially inappropriate behavior and many others," says Christina Myers, Ph.D., a professor in the Department of Neuro-oncology.
"Unfortunately, even subtle impairments of neurobehavioral functioning can reduce the patient's ability to function in his or her usual family and social roles," she says. For example, Meyers says that the majority of brain tumor patients nationwide do not return to work, and many require a full-time or near full-time caregiver.
To help, Meyers and a team of neuropsychologists are assessing risk versus benefit of conventional and investigational agents. They are designing a wide variety of interventions, such as the use of cognitive rehabilitation to help patients compensate for impairments of learning and memory, and cognitive-behavioral therapy to maximize the patients' and their caregivers' adjustment and coping skills. In addition, they are conducting clinical trials that examine the effects of a number of pharmacologic agents to help alleviate neurocognitive symptoms or to protect the brain to avoid them. They are also looking at potential genetic reasons why some brain tumor patients develop more severe neurocognitive symptoms than others, to allow treatment modfications for those that may be at risk.
Until a decade ago, the focus in cancer was to treat and cure the disease. Now we understand that quality-of-life issues are a part of cancer treatment, Meyers says.
"Our overriding goal is to help people be as independent and as high-functioning as possible before and after treatment," she says.
Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
Published on PsychCentral.com. All rights reserved.