Pharmacodynamic Study of Miransertib in Individuals with Proteus Syndrome

American Journal of Human Genetics
Kim M Keppler-NoreuilLeslie G Biesecker

Abstract

Proteus syndrome is a life-threatening segmental overgrowth syndrome caused by a mosaic gain-of-function AKT1 variant. There are no effective treatments for Proteus syndrome. Miransertib is an AKT1 inhibitor that, prior to this study, has been evaluated only in adult oncology trials. We designed a non-randomized, phase 0/1 pilot study of miransertib in adults and children with Proteus syndrome to identify an appropriate dosage starting point for a future efficacy trial using a pharmacodynamic endpoint. The primary endpoint was a 50% reduction in the tissue levels of AKT phosphorylation from biopsies in affected individuals. We also evaluated secondary efficacy endpoints. We found that a dose of 5 mg/m2/day (1/7 the typical dose used in oncology) led to a 50% reduction in phosphorylated AKT (pAKT) in affected tissues from five of six individuals. This dose was well tolerated. Two of the six efficacy endpoints (secondary objectives) suggested that this agent may be efficacious. We observed a decrease in a cerebriform connective tissue nevus and a reduction in pain in children. We conclude that 5 mg/m2/day of miransertib is an appropriate starting point for future efficacy trials and that this agent shows promise of therapeutic ef...Continue Reading

Citations

Apr 25, 2020·Cold Spring Harbor Molecular Case Studies·Anna BuserLeslie G Biesecker
Jan 23, 2020·BMC Medical Genetics·Xiaoyun ZengLingling Xu
Apr 29, 2020·Nature Reviews. Cancer·Pau CastelFrank McCormick
Sep 20, 2020·ESMO Open·Byung Woog Kang, Ian Chau
Jul 10, 2020·Neuro-oncology Advances·Andrea M Gross, Brigitte C Widemann
Feb 6, 2020·Cold Spring Harbor Molecular Case Studies·Leslie G BieseckerBrian Schwartz
Apr 2, 2020·Médecine sciences : M/S·Quitterie Venot, Guillaume Canaud
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Feb 27, 2021·Frontiers in Surgery·Ethan J KilmisterSwee T Tan
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Feb 9, 2020·Annales de dermatologie et de vénéréologie·A Phan
Oct 16, 2021·Cold Spring Harbor Molecular Case Studies·Christopher A OursLeslie G Biesecker

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