Aggressive brain tumors coming from the brain’s supporting glial cells, gliomas account for about a third of all brain tumors. They have the highest incidence and mortality rate among primary brain cancer patients, spurring an urgent need for effective treatments. While antidepressants already available could lower the risk of gliomas, there was little evidence to support their use in patients. Scientists at EPFL have discovered that tricyclic antidepressants combined with anticoagulant drugs can actually decelerate gliomas by causing the cancer cells to eat themselves.
Gliomas arise from the glial cells when they begin to grow uncontrollably. Normally, glial cells keep the brain’s neurons in place and help them function properly. There are three types of glial cells, and glioma tumors can contain a mixture of them.
There is currently little in the way of treatment for gliomas. Since the early 2000s, scientists have considered tricyclic antidepressants as a way to lower the risk of gliomas, but a small clinical trial showed them to offer little benefit to glioma patients.
The laboratory of Douglas Hanahan at EPFL approached the problem by combining tricyclic antidepressants with anticoagulant drugs (blood thinners). A study designed and led by Ksenya Shchors screened anti-depressants in combination with several commercially available drugs known to have similar effects on glioma cells. It revealed anticoagulants as the most likely ally.
The team determined the effects of the two drugs in mice with gliomas. The researchers gave the animals a combination therapy with different doses of the drugs. The antidepressant was administered orally, and the anticoagulant was injected 10 to 15 minutes later, and each combination therapy ran for five consecutive days.
The results showed that the drugs disrupt a biochemical pathway in the glioma tumor cells that controls a mechanism known as “autophagy,” which literally means “to eat oneself.” Low-level, controlled autophagy is a recycling mechanism that actually helps the cell to survive under stressful conditions.
The two drugs remove control in two different places along the autophagy pathway. Each drug can stimulate autophagy by itself, but neither has any significant impact on the mortality of the mice with glioma. Nonetheless, when the scientists combined the two drugs, the lifespan of the mice doubled. The team is now making plans for early clinical trials.
Douglas Hanahan, who warns that it is not clear yet if patients would benefit from such treatment, is optimistic: “It is exciting to envision that combining two relatively inexpensive and non-toxic classes of generic drugs holds promise to make a difference in the treatment of patients with lethal brain cancer. This strategy is at an early stage and requires further considerably more work to assess its full potential.”