Gliomas are aggressive brain tumors arising from the brain’s supporting glial cells. They account for about a third of all brain tumors, and hold the highest incidence and mortality rate among primary brain cancer patients, creating an urgent need for effective treatments. Certain antidepressants already in the market could lower the risk of gliomas, but there has been little evidence to support their use in patients. Now, scientists at EPFL have discovered that tricyclic antidepressants combined with anticoagulant drugs can actually slow down gliomas by causing the cancer cells to eat themselves. The study is published in Cancer Cell.

Gliomas arise from the supportive cells of the brain, called “glial cells” when they begin to grow uncontrollably. The normal function of glial cells are to keep the brain’s neurons in place and help them function properly. There are three types of glial cells, and glioma tumors often contain a mix of these.

Despite their aggressiveness and high mortality, there is currently little in the way of treatment for gliomas. Since the early 2000s, scientists have considered a category of antidepressants – called “tricyclic” – as a potentially new drug that could lower the risk of gliomas. However, a small clinical trial showed them to offer little benefit to glioma patients.

Making gliomas eat themselves
The lab of Douglas Hanahan at EPFL approached the problem by combining tricyclic antidepressants with anticoagulant drugs (blood-thinners). In a study designed and led by Ksenya Shchors, the scientists screened anti-depressants in combination with several commercially available drugs known to have similar effects on glioma cells. The screening revealed anticoagulants as the most likely ally.

The team investigated the effects of the two drugs in mice with gliomas. The animals received a “combination therapy”, where they were given different doses of the drugs. The antidepressant was given orally, while the anticoagulant was injected 10-15 minutes later. Each combination therapy ran for five consecutive days.

The results showed that the drugs work together against the cancer cells. Specifically, 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 survive under stressful conditions.

The two drugs remove control in two different places along the autophagy pathway, causing the cells to virtually eat themselves alive. Although each drug can stimulate autophagy by itself, neither has any significant impact on the mortality of the mice with glioma. But when the EPFL scientists combined the two drugs, the lifespan of the mice doubled.

“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,” says Douglas Hanahan. However, he warns that it is not clear yet if patients would benefit from such treatment. “This strategy is at an early stage and requires further considerably more work to assess its full potential.” Following up on this, the team is now making plans for early clinical trials.

This work was supported by grants from Fondation S.A.N.T.É. and the School of Life Sciences at EPFL.

Shchors K, Massaras A, Hanahan D. Dual Targeting of the Autophagic Regulatory Circuitry in Gliomas with Repurposed Drugs Elicits Cell-Lethal Autophagy and Therapeutic Benefit. Cancer Cell 28, 1–16 October 12, 2015. DOI: http://dx.doi.org/10.1016/j.ccell.2015.08.012

Lionel Pousaz, EPFL Press Service, email@example.com or +41 79 559 71 61

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