Dual Targeting of the Autophagic Regulatory Circuitry in Gliomas with Repurposed Drugs Elicits Cell-Lethal Autophagy and Therapeutic Benefit

Shchors K, 2015, Cancer Cell (Link to Abstract)

This publication outlines multiple related and progressive experiments. Firstly, the authors found that tricyclic antidepressants (TCA) can reduce the progression of low grade gliomas to GBM in a mouse model but does not change the progression or survival in mice who present with GBM. Then, an in-vitro assay measuring proteins generally degraded by autophagy found that TCAs promote autophagy in glioma cells. A high-throughput screen was then done to find a complementary drug that could accentuate the regulatory effect of TCAs on autophagy. Ticlopidine – an anti-platelet agent – had the best activity in this screen through its inhibition of P2Y12 which upregulates cAMP and promotes autophagy. They finally tested the combination of these drugs in various in-vitro and in-vivo model finding positive effects on autophagy and increased tumor killing and animal survival.

*Since GBM is so notoriously difficult to treat, inventive studies are needed. Approaches such as this one that target relatively uninvestigated biological pathways using drugs with already-established safety profiles that are off-patent is a promising way to get new effective treatments to clinic quickly.