Promising Developments in Treating Malignant Glioma

By Maciej S. Lesniak, M.D., associate professor of surgery and director of neurosurgical oncology and the Brain Tumor Center, The University of Chicago Medical Center

Although the prognosis of patients with malignant glioma has improved during the past decade, therapies currently under development are likely to improve the treatment of this devastating disease even more. The pre-clinical and clinical studies outlined below are highly promising:

Immunotherapy

The ability to engage the immune system, which usually protects us from infections, to control or perhaps even eradicate malignant brain tumors is gaining increasing attention. Two therapies are especially promising. DCVax (developed by Linda Liau at UCLA), a vaccine based on the use of dendritic cells, has already received regulatory approval in Switzerland and is completing clinical trials in the United States. The second vaccine, CDX-110 (John Sampson, Duke University), which involves taking advantage of a novel antigen expressed on gliomas—EGFRvIII—has shown equally promising results in early preclinical trial and is currently in Phase II/III human clinical trials.

Gene Therapy

The use of gene therapy for malignant brain tumors is a new development. One approach currently in trials (E.Antonio Chiocca, Ohio State, and I) uses an adenoviral vector engineered to express the Herpes thymidine kinase gene (AdV-tk) in the tumor, followed by an antiherpetic drug, valacyclovir, to kill it. The hypothesis is that this combination therapy can be safely delivered and will lead to improvement in the clinical outcome for patients with newly diagnosed malignant gliomas, including glioblastoma multiforme (grade 4, the most severe cancers) and anaplastic astrocytomas (grade 3). Two other promising vectors are likely to enter trials in the near future; one involves a replication-competent adenoviral vector (Ad24-RGD) developed by Dr. Juan Fueyo at M.D. Anderson Cancer Center and a second (CRAd-S-pk7) that is currently completing preclinical studies in my laboratory at the University of Chicago. (See more on gene therapy below.)

Chemotherapy

The promising results obtained with the use of temozolomide (Temodar) have prompted several trials that use this drug in combination with another agent. A multi-institutional trial involving Avastin (an anti-angiogenic drug, blocking the growth of blood vessels) in combination with temozolomide is ongoing. Other trials involve the use of temozolomide in combination with retinoic acid, thalidomide, Gliadel wafers, topotecan, and several others agents that can inhibit certain tumor pathways.

Local delivery of chemotherapeutic agents (directly to the brain tumor) is also under active investigation, and drugs such as paclitaxel (Oncogel) are in phase I (safety) human trials at the University of Chicago and several other institutions.

 

Targeted Therapy against Glioblastoma Multiforme and GBM Stem-Like Cells

By Gary L. Gallia, M.D., Ph.D., assistant professor of neurosurgery and oncology and director of minimally invasive and endoscopic neurosurgery at Johns Hopkins University School of Medicine

A tremendous amount of research over the past decade has increased our understanding of the genetic alterations that are present in patients with malignant brain tumors. These genetic alterations have defined specific pathways that are crucial for the tumor to grow. Many laboratories have not only identified novel mutations but have characterized the effect of these mutations.

For example, a commonly activated signaling cascade in this malignancy is the Akt pathway. This pathway (which can be activated by many alterations including genomic amplification of EGFR, PTEN deletion, or PIK3CA mutation) has been shown to be important in the start and development of gliomas. Deciphering such mutations and their altered pathways has led to new, targeted approaches to treating people with malignant gliomas.

The goal of targeted therapy is to be selective: inhibit tumor cells without significantly affecting normal brain cells or the cells in the rest of the body. Many different targeted approaches are being developed including drugs, monoclonal antibodies, immune-based therapies and small molecule inhibitors targeted at specific proteins. Many of these are in various stages of clinical trials and others are in laboratory development.

Accumulating evidence in the past few years has suggested that a small ratio of “stem-like precursors” exist in malignant gliomas. These cells display extensive self-renewal both in the laboratory and in animal model systems and are multipotent (able to differentiate into other cells found in the nervous system). This population of cells is highly tumorigenic (capable of causing tumor cells) and has been shown to be resistant to radiation and chemotherapy. Targeting this fraction of cells within the tumor may result in longer survival when compared with other therapies that may not effectively kill this population of cells.

Many laboratories including ours at Hopkins have isolated these tumor stem-like cells from patients with malignant brain tumors. Our group has characterized the genomic signature of these cells and found several genes upregulated (increasing in number of receptors to a certain stimulus) in this population. We are currently designing and evaluating therapeutics to target this stem-like population of cells. An interesting approach to target these stem-like cells is based on their ability to be differentiated; a recent study performed by scientists and clinicians at Johns Hopkins and the University of Milan has demonstrated the efficacy of differentiation therapy in a preclinical animal model.

 

More information:

Malignant Brain Tumors—A Synopsis by Michael D. Walker, Baltimore Cancer Research Center, for the Cancer Journal for Clinicians (PDF)

The Central Brain Tumor Registry of the United States (CBTRUS) is a not-for-profit corporation established to provide a resource for descriptive statistical data on all primary brain tumors irrespective of behavior.

Dana Guide to Brain Health: Brain Tumors, a section of our comprehensive reference for regular readers.

 
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Gliomas: The Latest Research

A universally fatal disease has become treatable, with hope of cure for some. And a raft of promising new approaches seem likely to increase that hope.
May 29, 2008

By Don M. Long, M.D., Ph.D., distinguished service professor in the department of neurology, The Johns Hopkins Hospital

Treating gliomas is difficult, but new and experimental treatments are extending the time people who develop these brain cancers can expect to survive. And treatments now in the lab and early testing have doctors and patients talking of cure.

Gliomas are tumors derived from cells in the brain called glia, which maintain and nourish nerve cells. As with other types of cancer, cancers of the glia are classified by type and by severity, but for gliomas the familiar words “malignant” and “benign” have a different meaning.

Some cancers of other organs are called malignant because they cause death by spreading throughout the body. Brain tumors rarely spread in this way. For brain tumors, the word malignant means they cause death because they grow (or grow back) rapidly in the same place where they originate, not because they affect other organs. The most malignant tumors are called glioblastoma multiforme. Less rapidly growing tumors look different under a microscope and are called anaplastic astrocytomas. The third type is benign astrocytomas. Another way to grade the tumors is by numbering: Grades 1 and 2 are benign; though 2 grows faster than 1; grade 3 is malignant but not the worst; grade 4 (the glioblastoma) is the most malignant.

Elsewhere in the body benign tumors can be cured by completely removing the tumor and, sometimes, a bit of the healthy tissue surrounding the tumor just to be sure. This does not often work for brain tumors for two reasons: In the brain, the location of the tumor often means even benign tumors cannot be removed without unacceptable damage to the patient. These tumors also infiltrate normal brain tissue; if all affected brain tissue were removed, the person would suffer severe neurological injury, making the cure as bad as the disease.

Thus, “benign” in brain tumors often doesn’t mean curable, but only that cancer’s growth will be slower. Patients may live for years with benign gliomas, but malignant astrocytomas  and glioblastomas are usually fatal within two years with treatment and often within weeks if untreated.

Early work: Drugs and radiation

Harvey Cushing, the founder of neurosurgery, and his famous neuropathology colleagues Louise Eisenhardt and Orville Bailey, were the first to categorize gliomas into an understandable scheme. For some 30 years after the first attempt to remove a glioma (by Rickman Godlee in London in 1884), neurosurgeons could remove the tumors only partially to provide temporary relief. The tumors always recurred and nearly all patients died.

In the early 1960s Joseph Galicich, Lyle French and I (with several collaborators) introduced a new drug, dexamethasone, to treat the swelling of the brain that often surrounds this tumors. The brain swells because fluids leaks from the tumor and the injured sections throughout blood vessels into the normal brain. This cerebral edema may be a more serious, acute problem than the tumor itself, because the area of swollen brain can be bigger than the tumor. Brain tumor patients often die from the edema, not the tumor.

Treatment with steroids such as dexamethosone shrinks the swelling. Steroids can dramatically reduce swelling, providing both extra time and brain protection for other treatments. Steroid treatment was the first great breakthrough to help patients with malignant tumors.

Edema, steroids and removing at least some of the tumor are all important because the skull is a closed box with limited capacity. As the tumor grows and the brain swells, the pressure in the box (skull) goes up, leading to severe headache, coma and death. At least partial removal of the tumor and shrinking the swollen brain prevents this progression. Patients improve, and there is time to try other treatments.

The next major advance came in 1978 when Michael Walker, who directed the Baltimore Brain Tumor Research Center, and his colleagues proved that radiation treatments (X-ray therapy) significantly prolonged life for patients with malignant astrocytomas. Then standard treatment became steroids, surgery to remove as much tumor as safe, followed by radiation.

Zeroing in on the tumor itself

During the late 1960s, throughout the ’70s and for most of the ’80s, brain tumor therapy research focused on trying new drugs to kill tumor cells. This approach was showing definite progress with many kinds of cancers but for the most part failed with malignant gliomas.

After watching many of these trials fail, only to be repeated with more of the same drug and fail again, I decided in 1982 that the newly founded John Hopkins Neuro-oncology Center should explore new approaches. I was fortunate to recruit Dr. Henry Brem to head the new center. Henry had been a fellow in neurosurgery and ophthalmology at Hopkins earlier in his career. He was finishing neurosurgery training at The New York Neurological Institute at Columbia and came with two revolutionary new ideas:

Anti-angiogenesis: “Angiogenesis” is the creation of new blood vessels. Attacking tumors by preventing the growth of blood vessels they need to feed and grow was proposed in 1971 by Judah Folkman of Harvard and has been intensely studied by Dr. Brem and many others. Promising new therapies are now appearing.

Prolonged local chemotherapy: The concept of local therapy (delivered directly at the tumor site) as opposed to systemic chemotherapy (delivered through the bloodstream to the tumor) was original to Dr. Brem and Dr. Robert Langer, who in the mid-1970s invented the polymer substrates that make slow-release local chemotherapy possible. After extensive clinical trials, in 1995 Dr. Brem and many collaborators showed that Gliadel (the local anti-cancer agent) significantly prolonged life after surgery for patients with glioblastoma.

Now, surgery for tumor removal that is as complete as possible, radiation, and Gliadel all are standard therapies. A new drug, Temodar, also is effective and looks promising as both an adjunct and alternative to Gliadel.

Future directions

In spite of these advances, malignant gliomas still are dangerous tumors and most patients will not survive them beyond a few years. Benign gliomas slowly grow, producing disabilities, and eventually are also fatal. Surgery might extend survival 9 or 10 months. Gliadel extends this by two to three months, on average. But there is a little more hope now—and there is a small group of people who survive much longer.

Current therapy provides at least some hope of meaningful survival and cure. Still it is clear that we need more effective treatment for gliomas of all kinds. Development of better therapies is critical.

There are some new avenues of treatment that appear to be especially promising (see sidebar stories). There also are newer forms of radiation that may be helpful. The Gamma Knife, the Cyber Knife and a focused linear accelerator beam are examples of radiation therapies that can closely target the tumor, delivering less (or no) radiation to the surrounding normal brain. The use of radiation with protons has been restricted to two centers but soon will be available commercially. Much research is under way in how to make tumor cells more sensitive to radiation. All have great promise to improve outcomes for patients with gliomas.

I think the genetic approaches exemplified by the work of Dr. Lesniak (first sidebar) and the novel techniques described by Dr. Gallia (second sidebar) are excellent examples of the future for treatment of malignant (and other) gliomas. Identifying and mass producing viral vectors that are safe is key to effective gene therapy in this area. Vaccines might become reality. More research with local delivery of improved drugs should follow Gliadel. Some or all of these newest concepts soon should offer more regular, dramatic successes than we see now.

Surgery, steroids, radiation therapy and local chemotherapy have all improved survival rates by small increments. A universally fatal disease has become treatable, with hope of cure for some. It is likely that the new treatments will provide a much greater chance of cure for all.