Researchers funded by the National Institute of Neurological Disorders and Stroke (NINDS) have found that an organ transplant drug might one day be used to treat meningioma, a type of brain tumour.
The drug also could be used to treat neurofibromatosis type 2, a rare disease associated with meningiomas and other benign tumours of the nervous system.
In a study published in Molecular and Cellular Biology, the researchers show that rapamycin – an immunosuppressant used to prevent organ transplant rejection – can shrink meningioma cells grown in the laboratory.
Meningiomas account for 20–30 percent of all brain and spinal cord tumours. They arise from cells in the thin layers of connective tissue that surround the brain and spinal cord, called the meninges. Although most meningiomas are benign, they can cause neurological problems by compressing brain tissue. Surgery is usually effective, but, in some cases, the tumours are not accessible or may persist despite surgery.
“Pharmacological therapies are desperately needed,” says Vijaya Ramesh, PhD, an associate professor of neurology at Harvard Medical School and Massachusetts General Hospital (MGH) in Boston. Dr Ramesh is the senior author on the new study; other key authors include James F. Gusella, PhD, Director of the Center for Human Genetic Research at MGH and a professor of neurogenetics at Harvard, and Marianne F. James, PhD, a neurology instructor at Harvard. The study received additional funding from the National Institute of Mental Health (NIMH), the S. Sydney De Young Foundation and Neurofibromatosis, Inc.
Deficiency of a gene called NF2/merlin is the cause behind most cases of isolated (sporadic) meningioma and all cases of neurofibromatosis type 2. Neurofibromatosis type 2 occurs when a person has only one functional copy of the NF2 gene from birth. Sporadic meningioma occurs when meningeal cells in the brain lose both copies of NF2 during a person’s lifetime. These effects make NF2 a “tumour suppressor” gene, but until now, researchers knew little about how NF2 suppresses tumours or how to approach possible drug treatments.
Dr Ramesh and her team made a fortuitous discovery. In a 2008 study, they found that NF2-deficient meningioma cells grow larger than normal cells. They recalled that this is also a feature of tumour cells found in people with tuberous sclerosis complex (TSC), a disease in which benign tumours can grow in nearly any tissue, including the eyes and brain. Recent studies have shown that the tumours in TSC are triggered by abnormal activity of a protein called mTOR, which promotes cell growth and is inhibited by rapamycin. Dr Ramesh’s team thought that mTOR might also play a pivotal role in meningioma.
In their new study, they found that mTOR is abnormally active in NF2-deficient cells derived from patients with meningioma. When they used a technique called RNA interference (RNAi) to block the activity of NF2 in normal meningeal cells, they observed an increase in mTOR activity and an increase in cell growth. Treatment with rapamycin slowed this growth and reversed it over the course of several days.
The researchers also found that when rapamycin shuts down mTOR, it indirectly activates a signalling pathway called PI3K-Akt, which has been associated with malignancy. They propose that rapamycin in combination with PI3K-Akt inhibitors might safely reduce the growth of meningioma cells.
Preparations are underway to create a mouse model of benign meningioma that will be used to test these treatments, Dr Ramesh says. As in humans, mice that lack the NF2 gene from birth have a risk of meningioma, but the number of mice that actually develop meningoima is small and the tumours themselves are microscopic. Dr Ramesh and her colleagues will use their RNAi technique to suppress NF2 in human meningeal cells, and then implant the cells into the mouse brain.