Battling Glioblastomas

Joon H. Uhm, M.D., neurologist and neuro-oncologist at Mayo Clinic in Minnesota, is at war, literally and figuratively, against a formidable opponent: glioblastoma. The average survival rate for patients with a glioblastoma who have aggressive treatment, including surgical resection, radiation and chemotherapy, is about 14 months. Only 27 percent survive two years.

A glioblastoma is called a "grow-and-go" tumor — it grows at an extremely rapid rate in a given brain site, but it also moves to new sites within the brain. It is no wonder that Dr. Uhm describes the fight in military terms. "It's a battle that takes a huge team effort on both the patient care and research fronts," he says. "Across Mayo's three sites, we have assembled the team we need to address both the growth and movement properties of glioblastomas."

Three-dimensional surgical model help Mayo neurosurgeons plan the safest surgical approaches.

Immunotherapy

The latest member of that team brings a new weapon to Mayo's arsenal: immunotherapy.

Ian F. Parney, M.D., Ph.D. joined the Department of Neurosurgery at Mayo Clinic in Minnesota in summer 2008. An expert in surgical management of brain tumors and in immunologic research, his goal is to harness the power of the immune system to create a therapeutic vaccine. Called a dendritic vaccine, it would stimulate an immune response against glioblastoma tumor cells and disrupt their ability to suppress the immune system itself. Dr. Parney is collaborating with immunologist Allen B. Dietz, Ph.D., head of Mayo's Human Cellular Therapy Laboratory.

"One of the reasons I came here," says Dr. Parney, "is that Mayo has the infrastructure to take this research from the laboratory to the patient. Making a vaccine that is safe for patients is a difficult and resource-intensive process. Mayo is unique in having an institutional human cell therapy laboratory capable of producing clinical-grade cellular treatments."

The other reason Dr. Parney came to Mayo was "the opportunity to work with a renowned group of clinicians who provide a multidisciplinary approach to every patient, every time, all the time. We provide treatment planning options for patients—surgical resection, radiotherapy, and chemotherapy—and evaluate and follow-up patients after their treatment." The integrated approach to practice includes weekly teleconferencing across Mayo's three sites to discuss difficult cases as well as ongoing research.

Dr. Uhm adds that the neurologists, neurosurgeons, medical oncologists, neuroradiologists, radiation oncologists, neuropathologists, and physical medicine and rehabilitation physicians who make up the CNS Tumor Practice Integration Team work continuously to optimize patient care, including fast-tracking and streamlining the initial evaluation for patients with aggressive tumors like glioblastoma.

Research and Treatment: A Single Effort

In the war against glioblastomas at Mayo Clinic, it is difficult to distinguish between the research and treatment fronts, because they have merged into a single effort. "Our first priority is patient care," says Dr. Uhm. "All our research has direct relevance to the patient, and because most of our clinicians are conducting research, the research and clinical care complement each other."

Dr. Uhm cites the programmatic SPORE (Specialized Projects of Research Excellence) grants as an example. Led by Brian P. O'Neill, M.D., a neuro-oncologist at Mayo Clinic in Minnesota, and funded by the National Cancer Institute (NCI), these projects focus on clinical trials for new drugs, new diagnostic tests, and molecular prognostic indicators to determine which patients will benefit from a given drug.

Ongoing Research

While much of Mayo's research focuses on the growth properties of glioblastomas, Dr. Uhm has a specific interest in the "go" properties. His colleague, Joseph C. Loftus, Ph.D., at Mayo Clinic in Arizona, has isolated a protein that plays a key role in enabling a glioblastoma to move from site to site in the brain. As a clinician, Dr. Uhm hopes to help bring Dr. Loftus's critical findings to the bedside. In conjunction with a pharmaceutical company, this physician-scientist team is developing a clinical trial for a drug that would target the protein and prevent tumor migration.

Other approaches to tumor treatment under study at Mayo are oncolytic viruses, which can infect and kill tumor cells while leaving normal cells intact. Evanthia Galanis, M.D., an oncologist at Mayo Clinic in Minnesota, and her colleagues are evaluating the potential of oncolytic viruses to destroy glioblastomas.

New methods of attacking a glioblastoma must be wed to research that determines who will benefit from treatment. As Dr. Uhm explains, tumors from two different patients may look the same under the microscope; one patient's tumor may respond well while the other may not. Jann N. Sarkaria, M.D., a radiation oncologist at Mayo Clinic in Minnesota, and colleagues have found that certain tumors express a protein that prevents the tumor from responding well to standard chemotherapy regimens. Knowing which tumors do and which do not have this protective protein will help Dr. Sarkaria's team identify patients most likely to benefit from certain types of chemotherapy.

Clinical Trials

The goal of determining the molecular basis and action of glioblastomas, their effect on the immune system, and their response to oncolytic viruses, molecular manipulation, and immunotherapy is to generate new treatments. As Dr. Parney notes, "Mayo can provide experimental treatments through the clinical trials offered through Mayo Clinic Cancer Center and North Central Cancer Treatment Group (NCCTG)."

NCCTG is a national clinical research group funded by the NCI. Researchers across Mayo's three sites contribute to the development, execution, and review of all high-priority NCI-funded trials. Kurt A. Jaeckle, M.D., a neuro-oncologist at Mayo Clinic in Florida, where basic science and gene therapy cancer research is ongoing, chairs the NCCTG's Neuro-oncology Committee.

Other avenues for participation in clinical trials include institutionally funded trials through the Mayo Clinic Cancer Center, the only NCI-designated National Cancer Center with sites in three geographic locations. As Dr. Uhm says, "The motto 'One Cancer Center; Three Front Doors' is an apt description of Mayo's cancer treatment and research integration of which our brain tumor program is an excellent example."

Most new drugs, including the immune-based therapies for glioblastomas, are combined with radiotherapy, explains Dr. Uhm. Radiation oncology researchers at Mayo are continuously developing new protocols to complement advances in chemotherapy.

PET scan of glioblastoma multiforme

Surgical and Imaging Advances

Dr. Parney is animated as he describes the latest imaging technology available at Mayo, which he says helps in surgical planning, makes surgery safer and improves the possibility of preserving function. Examples include functional MRI (fMRI); diffusion tensor imaging, which allows mapping of white matter tracts; image-guidance technology; and the ability to correlate functional imaging with intraoperative electrophysical mapping.

Intraoperative MRI with a high-field-strength (1.5 Tesla) magnet allows surgeons to re-register the image-guidance system after the tumor has been removed to compensate for brain shift during surgery. Dr. Parney notes the shared enthusiasm among the radiologists and physicists who participate in Mayo's imaging research for future advances such as intraoperative fMRI.

Reviewing Mayo's war against glioblastomas, Dr. Uhm concludes, "We have major research invested in determining what makes a glioblastoma grow-and-go and in clinical trials to target those two components. Now, as we advance toward a therapeutic vaccine, we are working to harness the surveillance capabilities and weaponry of the immune system in our fight against these aggressive and deadly tumors."