Case study: Clinical trials of existing medications
Introduction
PHTS is caused by constitutive PTEN variants which downregulate the activity of the PI3K/AKT/mTOR signalling pathway. Given the role of this pathway in key biological processes, including cell proliferation, apoptosis, metabolism, and angiogenesis, multiple drugs targeting this pathway, including rapalogs, have already been approved for a range of conditions including cancer and conditions related to PHTS, such as Tuberous Sclerosis Complex. However, there are no health-authority approved drugs for PHTS.
To date PTEN Research has co-funded two clinical trials of mTOR inhibitors everolimus and sirolimus, detailed below.
We hope to announce new clinical trials in 2026.
Project 1 key facts
Project title: RAD001 and Neurocognition in PTEN Hamartoma Tumor Syndrome
Type of study: Clinical trial (NCT02991807)
Lead researcher: Prof Mustafa Sahin
Institution: Boston Children’s Hospital, USA
Project start: June 2017 Completed: December 2021
Project 1 goals
To assess the safety and efficacy of everolimus on neurocognition and behaviour in PHTS.
Project 1 overview
This phase II, randomised, double-blind, placebo-controlled trial of everolimus treatment recruited individuals with a constitutional PTEN variant (n=46), aged 5 to 45 years. The study involved a 6-month randomised treatment phase followed by a 6-month open label phase.
Project 1 outcomes
This trial was completed in December 2021. Results showed that everolimus is well tolerated by individuals with PHTS and, although the primary efficacy endpoint did not reveal improvement, several secondary efficacy endpoints moved in the direction of improvement.
The following publications have resulted from work associated with this grant:
- A randomized double-blind controlled trial of everolimus in individuals with PTEN mutations: Study design and statistical considerations
- A randomized controlled trial of everolimus for neurocognitive symptoms in PTEN hamartoma tumor syndrome
- Sensitivity Analysis of the Efficacy of Everolimus for Neurocognitive Symptoms in PTEN Hamartoma Tumor Syndrome
Project 2 key facts
Project title: Sirolimus for Cowden Syndrome With Colon Polyposis
Type of study: Clinical trial (NCT04094675)
Lead researcher: Dr Peter Stanich
Institution: Ohio State University, USA
Project start: August 2019 Completed: June 2025
Project 2 goals
To assess if treatment with sirolimus for one year could reduce colon polyps in individuals with a constitutive PTEN variant.
Project 2 overview
This single-centre phase II, open-label, pilot trial enrolled 5 out of 10 planned participants, with two completing the study course.
Project 2 outcomes
This trial was completed in June 2025. For the two participants completing the study, polyp burden decreased but there was no change in polyposis staging. Two participants had significant side effects likely related to the therapy.
Larger studies are required to further characterise the efficacy and safety of sirolimus in PHTS-associated GI polyposis.
The following publication resulted from work associated with this grant:
· Sirolimus for Colon Polyposis in PTEN Hamartoma Tumor Syndrome