Brain Tumor Research
Brain tumors will not be defeated by simply making conventional treatments stronger, but by discovering new ways to break down the genetic, molecular, cellular and immunologic mechanisms that allow them to exist. Treatment teams and research scientists work together at Cedars-Sinai Medical Center to provide the highest level of care currently available while step by step advancing the science of innovative therapies.
The Maxine Dunitz Neurosurgical Institute was established at Cedars-Sinai in 1997 to focus on finding treatments and cures for brain tumors and other disorders of the central nervous system. Research scientists, neurologists and neurosurgeons collaborate in specialized laboratories and programs to study:
- The blood-brain barrier, the defense mechanism in small blood vessels that protect the brain from toxins but also prevent most forms of chemotherapy from reaching brain tumors.
- Genes that contribute to the development of brain tumors, and ways to defeat them.
- Gene therapies that may prevent or treat brain tumors.
- Interactions between brain tumors and the immune system, with an emphasis on boosting the immune system to fight tumors. An experimental vaccine [link to http://www.csmc.edu/pf_10138.html], now in clinical trials, is one part of this research effort.
- Stem cells. Certain “immature” cells (neural stem cells and neural progenitor cells) have the potential to become neurons of the central nervous system. Other stem cells (cancer stem cells) appear to be the mother cells from which cancer cells originate.
- New drugs and innovative molecular therapies that may literally disassemble the mechanisms within the cells of brain tumors. A new “nanoconjugate,” Polycefin, is expected to move into patient trials in the near future. [possibly link to article on how Polycefin works]
A relatively small but highly integrated and focused research center, the institute receives about $2 million in funding from the National Institutes of Health each year and has a strong base of support through a community organization called The Brain Trust that has raised about $11 million. As a result of these efforts, the research teams now publish more than 60 articles in major scientific journals each year. In recent years (2001, 2002, 2003, 2004, 2005, 2006, 2007, 2008) , the research teams:
- Found that up-regulation of laminin-8, a protein product of several genes, may be a critical step in brain tumor progression and the ability of a tumor to develop blood vessels needed for growth. Laminin-8 was associated with poor patient prognosis. (Cancer Research, July 15, 2001.)
- Documented in an animal study that they could circumvent the blood-brain tumor barrier (BTB) to selectively deliver drugs directly to the area of brain tumors without increasing delivery to normal brain tissue. Without intervention, the BTB prevents most of a cancer-killing medication from reaching the tumor. (Journal of Pharmacology and Experimental Therapeutics, June 2002.)
- Engineered neural stem cells, which have a natural ability to target and track glioma cells, to secrete interleukin 12. In this mouse study, inoculation with IL-12-secreting neural stem cells resulted in significant prolongation of survival. Not only did treated mice survive longer, they demonstrated a high level of long-term immunity when additional glioma cells were implanted three months after the first ones. (Cancer Research, Oct. 15, 2002.)
- Generated for the first time neural progenitor cells from whole adult bone marrow. If these neural stem cells can be transplanted to treat stroke, brain tumors and neurodegenerative disorders, they could provide a renewable source of stem cells, available from a patient’s bone marrow instead of the brain and without the ethical and tissue-rejection issues associated with the use of embryonic or fetal stem cells. While this study was conducted in rats, similar optimistic results have been seen in human tissue. (Experimental Neurology, December 2002.)
- Engineered neural stem cells to deliver TRAIL, a protein known for its cancer-fighting properties. In laboratory studies, unmodified TRAIL cells attacked human glioblastoma cells, with nearly all tumor cells being killed within 24 hours. TRAIL-secreting neural stem cells also resulted in significant cancer cell death, and the genetically engineered stem cells maintained their viability for as long as 10 days. (Cancer Research, Dec. 15, 2002.)
- Discovered that an antigen, Tyrosinase-Related Protein-2 (TRP-2), previously found in melanomas, is also expressed in glioma cells and could be used as a target of immunotherapy. (Journal of Immunotherapy, July/August 2003.)
- Reduced tumors’ ability to invade neighboring tissue by blocking the expression of laminin-8. This study supported the hypothesis that laminin-8 is involved in the spread of these malignancies and it reinforced the possibility that a therapy may be developed to arrest the tumors by targeting the gene. (Molecular Cancer Therapeutics, October 1, 2003.)
- Documented that recently produced cancer-fighting cells are the major determinant of prognosis and survival of glioma patients. While age at diagnosis has been the best predictor of tumor recurrence and survival, this research contributed to the recognition that a robust immune system is the underlying key – a younger person’s immune system is better able to fight cancer. Patients with high numbers of recently generated CD8+ T lymphocytes respond more favorably to immune therapy vaccine. (Journal of Immunology, November 1, 2003.)
- Described the type of neural stem cells that are able to track brain cancer cells as they migrate from a tumor to form new satellites, and described a mechanism that turns on the tumor-tracking activity. The stem cells are considered potential transporters to deliver cancer-killing agents. (Neoplasia, May/June 2004.)
- Identified three antigens that are expressed in glioblastoma cells and used them as targets for the dendritic cell vaccine. In laboratory studies and in a small patient trial, cancer-killing immune cells recognized glioma cells expressing the antigens, HER2, gp100, and MAGE-1, and the vaccine appeared to play a role in prolonging patient survival. The median length of survival of patients whose treatment included the vaccine was 133 weeks – about two and a half years. A similar group of patients receiving the same level of care but not the vaccine had a median survival of only 30 weeks – seven and a half months. (Cancer Research, July 15, 2004.)
- Reported that an optical device was able to quickly and accurately discriminate between brain tumor and normal tissue. If the technology continues to progress as anticipated, neurosurgeons will be able to shine a laser light during surgery to diagnose brain tumors instantaneously and discern the borders of tumors with greater precision than ever. Time-resolved laser-induced fluorescence spectroscopy is based on the fact that when molecules are stimulated by light, they respond by becoming excited and re-emitting light of varying colors that can be captured and measured. (Photochemistry and Photobiology, July/August 2004.)
- Found that over-expression of laminin-8 is a predictor of a tumor’s grade, its potential for recurrence, and the patient’s length of survival. (Cancer, August 2004.)
- Reported that the combination of immunotherapy and chemotherapy significantly slowed tumor progression and extended survival of patients with glioblastoma multiforme. The results suggest that chemotherapy synergizes with previous therapeutic vaccination to generate a uniquely effective treatment. Average length of survival was extended to about 26 months when patients received the combined therapies, compared to 18 months for those who received vaccine alone and 16 months for those undergoing chemotherapy alone. (Clinical Cancer Research, Aug. 15, 2004.)
- Isolated “cancer stem cells” from malignant brain tumors. These stem cells share the multi-potent and self-renewing properties of normal stem cells but instead ofproducing healthy cells, they propagate cancer cells in their own image. (Oncogene, Dec. 16, 2004.)
- Described the molecular mechanism that appears to make malignant brain tumors more vulnerable to chemotherapy after they have been treated with the dendritic cell vaccine. TRP-2, the protein fragment reported in gliomas in 2003, was identified as a potentially “powerful molecule” linking chemotherapy and immunology. The immune system recognizes TRP-2 as a foreign invader, making it a significant target for immunotherapy and making the tumor more vulnerable to follow-up chemotherapy. (Oncogene, August 2005.)
- Exploited a biochemical pathway to make gliomas much more sensitive to a drug and a natural process of cell death called apoptosis. (Journal of Biological Chemistry, published online Nov. 30, 2005.)
- Attached a newly discovered cytokine, interleukin 23, to neural stem cells derived from bone marrow, creating a tool to track and kill malignant brain tumors cells and provide long-term protection against their return. The animal study was expected to lead to a human trial in the near future. (Cancer Research, March 1, 2006.)
- Found in an animal study that the intratumoral injection of bone marrow-derived dendritic cells and interleukin 23 produced a strong systemic immune response with long-term protective effects. The approach may have therapeutic potential for treating human glioma and was expected to be the subject of an upcoming clinical trial. (Cancer Research, Sept. 1, 2006.)
• Documented that cancer stem cells are resistant to conventional chemotherapy and contribute to disease relapse. Theoretically, these cells are the ultimate source from which a tumor grows – and therefore, the ultimate target for therapies. (Molecular Cancer, Dec. 2, 2006.)
- Manipulated stem cells taken from adult human bone marrow to generate aggregates of cells called spheres that are similar to those derived from neural stem cells of the brain. The cells migrated and behaved like actual neural stem cells when transplanted into the brain tissue of chicken embryos. (Journal of Neuroscience Research, February 2007.)
- Found in a mouse study that two molecules existing in certain fruits and vegetables reduced levels of a protein that forms the sticky deposits that build up in the brains of patients with Alzheimer’s disease. The results may offer a new approach to therapy for the neurodegenerative disease. (Journal of Cellular and Molecular Medicine, online April 10, 2008.)
- Reported the results of a mouse study in which the interruption of a signaling pathway enabled immune cells from outside the brain to enter the brain to attack the sticky plaque buildup that occurs with Alzheimer’s disease. This could lead toanother new potential target for the treatment of Alzheimer’s. (Nature Medicine, June 1, 2008.)
- Used an engineered virus to deliver a protein that glows green when exposed to blue light (green fluorescent protein) to study gene delivery in developing “self-repair” strategies for Parkinson’s disease and other neurodegenerative disorders. (Neurobiology of Disease, June 2008.)
- Documented that medications such as Viagra and Levitra, commonly prescribed for erectile dysfunction, open the blood-brain tumor barrier and increase delivery of cancer-fighting drugs to malignant brain tumors. In laboratory animals, the drugs selectively increased drug transport to tumors without affecting normal brain tissue. (Brain Research, Sept. 16, 2008.)
- Correlated the “intensity” of a patient’s immune response and clinical outcome among patients participating in a Phase II dendritic cell vaccine trial for malignant brain tumors. This is believed to be the first study showing “direct and continual proportionality” between the strength of anti-tumor responses and clinical benefits in cancer patients. It may also be the first documentation of a definite immune response/patient outcome correlation that can be credited to tumor-altering therapeutic interventions. The findings give scientists a way to more quickly evaluated future vaccine-related research. (Cancer Research, July 15, 2008.)
- Identified a molecular mechanism (the Sonic Hedgehog signaling mechanism) involved in the development of brain cancer stem cells (isolated in adult brain tumors in 2004). Theoretically, this could offer a target for scientists seeking treatments that would kill malignant brain tumors at their source and prevent them from recurring. (Stem Cells, online Sept. 11, 2008.)
- Found a possible link between cilia – protrusions from cell surfaces that appear to act as antennae – and medulloblastomas, tumors of the cerebellum that occur in different forms in children and adults. A gene called the Stumpy gene, which was discovered by Cedars-Sinai researchers, affects the development of cilia and appears to play a significant role in the genesis of pediatric medulloblastoma. (Unpublished.)
One of the primary objectives at Cedars-Sinai is to efficiently translate new basic research findings into experimental patient treatments through The Johnnie L. Cochran, Jr. Brain Tumor Center.