Repurposing drugs for treating the neurobehavioral manifestations of PTEN hamartoma tumor syndrome.

PTEN hamartoma tumor syndrome (PHTS) is caused by mutation of PTEN and patients suffer from an increased risk of cancer and neurodevelopmental disorders. While treatment with mTOR inhibitors can alleviate some aspects, there remains a significant need for treatment of neurobehavioral symptoms in PHTS. Here, we describe a drug-repurposing program, screening >60 compounds targeting the PI3K/AKT/mTOR pathway. First, we interrogated altered signaling and morphology in a cell-line and primary neurons with PTEN-dysfunction, before further refining our compound selection using multielectrode recordings and MDCK assays. A final number of six compounds, with promising potency and propensity to cross the blood-brain-barrier, were tested in vivo in pharmacokinetic and proof-of-principle pharmacodynamic studies, and we observed that dual PI3K/mTOR inhibitors achieve effects comparable to or even surpassing those of standard mTOR inhibitors. In summary, our study showcases a combination of in vitro models providing a valid strategy for identifying drug-repurposing candidates to treat PHTS patients.