Cleveland Clinic researchers have identified a cellular pathway that cancer stem cells use to promote tumor growth in malignant glioma, an aggressive brain tumor. The research -- published in the July 8 issue of Cell -- also found that existing medications block this cancer-promoting pathway and delay glioma growth in animal models, suggesting a new treatment option for these often fatal brain tumors.
Malignant gliomas account for more than half of the 35,000-plus primary malignant brain tumors diagnosed each year in the United States. Unfortunately, the outlook for patients with malignant gliomas is poor. For patients with the most severe, aggressive form of malignant glioma (grade IV glioma or glioblastoma multiforme), median survival is 9 to 15 months with the best available therapies. These treatments include surgery followed by radiation therapy with the chemotherapy temozolomide followed by additional temozolomide treatment.
Although differences in tumors between people were known to exist, researchers have only recently begun to understand the importance of differences between cancer cells within the same patient. Groups of cells within a glioma which promote brain tumor formation in animal models -- called cancer stem cells -- have been identified. These cancer stem cells are often resistant to radiation and chemotherapy, making them an important target for developing new and effective disease treatments.
In a recently published manuscript, a team of Cleveland Clinic researchers -- led by Jeremy Rich, M.D., Chairman, and Anita Hjelmeland, Ph.D., of the Department of Stem Cell Biology and Regenerative Medicine of the Lerner Research Institute of Cleveland Clinic -- define a novel molecular pathway that cancer stem cells use to promote tumor growth. Cancer stem cells produce elevated nitric oxide, a molecule whose role in cancer is not well defined but which has been linked to therapeutic resistance, evasion of cell death, and enhanced proliferation. Nitric oxide is produced in cancer stem cells through increased levels of the enzyme nitric oxide synthase 2 (NOS2); decreasing the level or activity of this enzyme reduces cancer stem cell growth. When drugs inhibiting the NOS2 enzyme were given to mice with gliomas, the growth of the tumors was delayed. Using the National Institutes of Health supported database of glioma specimen data, they also found that increased levels of this enzyme are associated with decreased survival of glioma patients. Targeting this pathway could therefore provide benefits for glioma patients.
Current therapies for cancer have many side effects, because they rely on the increased sensitivity of the cancer cells to drugs which are toxic to normal cells. It is therefore important to consider the potential side effects of any new proposed cancer treatment. The current study did compare the levels of the enzyme NOS2 and the effects of its inhibitors in cancer stem cells and normal neural stem cells. Normal neural stem cells have some similar properties as cancer stem cells from gliomas but cannot form tumors. Only cancer stem cells were found to depend on the enzyme for their growth. Drugs inhibiting the NOS2 enzyme were evaluated in patients for the treatment of other diseases and had minimal toxicity. The authors suggest that these drugs may therefore be useful for enhancing the effects of current therapies without adding a lot of side effects. NOS2 inhibitors may thereby pose a potential therapeutic breakthrough for this lethal disease.
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