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Syncytia formation in primary glioma cells
Patients with malignant glioma, the most common and most aggressive form of primary brain tumor, have an average survival time of 12 to 16 months. With a high rate of recurrence, these tumors are resistant to conventional therapy, including surgery, radiation therapy, and chemotherapy. For all these reasons, glioblastoma is one of the key focus areas for Mayo Clinic's brain cancer research (see Neurosciences Update volume 5, number 4).
"A key focus of our effort is to translate promising laboratory findings into clinical trials, then, building on the clinical data, go back to the lab to create something we think is even better," says Evanthia Galanis, M.D., an oncologist with a special interest in neuro-oncology, especially glioblastoma research.
She and her colleagues are conducting pioneering work on the use of oncolytic viruses and novel targeted drug combinations. Her words highlight the interplay between the laboratory and clinical outcomes that exemplifies bench-to-beside or translational research. These familiar terms represent an ideal in which laboratory and clinical findings create a continuous loop of innovations and clinical applications to improve patient care. This goal, however, can be difficult to attain, particularly within a single institution. It requires integrated teams of researchers and clinicians and an infrastructure that provide the necessary equipment and support data analysis and clinical trials.
Mayo Clinic is fortunate that its own extensive infrastructure is supported by several major programs that further increase efficiency. Mayo is one of four institutions in the country to have a National Cancer Institute (NCI)–funded brain cancer Specialized Program of Research Excellence (SPORE). It also holds four other SPORE grants and participates in two more.
These grants, in turn, are supported by Mayo's NIH-funded Center for Translational Science Activities (CTSA) and Mayo's three-site, NCI-funded Cancer Center, one of the largest in the country. Finally, Mayo's leadership in the North Central Cancer Treatment Group (NCCTG), a cooperative clinical research group for development, execution, and review of high-priority NCI-funded trials, helps expedite novel treatments into trials.
"The theme in our brain cancer SPORE is pathogenesis-based prevention and treatment of gliomas, which involves understanding the mechanisms and identifying predictors," says Brian Patrick O'Neill, M.D., the Mayo neurologist who heads the brain cancer SPORE.
The SPORE is divided into four cores that support each phase from new initiatives to refining previous discoveries. "When Dr. Galanis's team wants specimens analyzed to understand the effects of a drug," Dr. O'Neill notes, "the clinical core provides the clinical background on each patient. The pathology core provides the diagnostic and pathology analysis, and the statistics core provides the data analysis. Thus, we have an economy of scale, driven and supported by a single institution."
The research by Dr. Galanis and her colleagues, highlighted in the following sections, exemplifies translational research in action.
Case reports in the 1970s suggested that natural infection with the measles virus (MV) led to spontaneous regression of hematologic malignancies in African children. Since then, the biogenetic mechanisms of the MV have been identified and have helped clarify its potential as an oncolytic agent. Building on this information, Dr. Galanis and colleagues discovered that a vaccine strain of MV causes glioma cells to fuse, thus triggering apoptosis or cell death. This agent is now in a clinical trial to assess its safety in treating glioblastoma.
During their investigation, the research team overcame a major challenge in using viral approaches to brain tumors — the limited ability to monitor the effect of the virus on a tumor in vivo — by engineering the virus to express the soluble marker carcinoembryonic antigen.
To better understand the virus's action in a nonartificial environment before human testing, Dr. Galanis's team, in collaboration with Jann Sarkaria, M.D., a radiation oncologist and head of the brain SPORE's animal core facility, implanted tumors extracted from patients directly into a series of animal models. In these models both the tumor and the virus performed as they do in humans. The effects were found to be positive and nontoxic.
The in vivo work dramatically expedited bringing the virus into human trials. Preliminary results suggest that it may inhibit tumor recurrence and, when used in combination with other targeted drugs, it may increase the oncolytic effects of both.
Bevacizumab is an example of a smart or targeted drug — a drug that exploits tumor-specific molecular changes. Glioblastomas tend to be very vascular and heavily dependent on blood supply to grow. Bevacizumab works by binding to vascular endothelium growth factor (VEGF) and preventing it from signaling.
VEGF is known to increase tumor blood supply, but, as Dr. Galanis points out, "while bevacizumab can lead to durable responses in recurrent glioblastoma, the patients invariably progress." She and her team hypothesized that for the treatment to be more effective, it was necessary also to block VEGF receptor signaling. They did so by combining bevacizumab with sorafenib, another targeted drug.
The team has also combined bevacizumab with dasatinib, a smart drug that helps block tumor cell invasion. They developed this combination because glioma cells in a significant percentage of patients escape the effects of bevacizumab and invade the brain to establish new tumors in distant sites. Both this combination and the bevacizumab-sorafenib combination are now in clinical trials through the NCCTG.
Another drug combination currently being tested through NCCTG includes the use of vorinostat with bortezomib. Vorinostat interferes with the coiling of a tumor's genetic material and has shown single-agent activity in patients with recurrent glioblastoma. It is hoped that this drug combination will further enhance this benefit.
Dr. Galanis adds, "In many of our trials, we give the therapy before scheduled surgery so we can examine the effect of the drug on the tumor itself. In all our trials, we try to correlate the baseline tumor specimens with their genetic characteristics and the patient's outcome to predict who will get the most benefit from the drug."
Supported by the extensive in-house infrastructure that molecular and gene-based investigations require, researchers like Dr. Galanis and colleagues across Mayo's three sites can collaborate in developing therapies, analyzing clinical outcomes, and conducting laboratory reassessments. In this way, they have generated novel drug combinations and pioneered novel therapies like oncolytic virus therapies and targeted drug combinations for expeditious entry into new clinical trials.
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