Pharmacodynamic Study of Miransertib in Individuals with Proteus Syndrome
Autor: | Paul Jarosinski, Staci Martin, Neera R. Nathan, Mohammadhadi Bagheri, Brigitte C. Widemann, Julie C. Sapp, Pamela L. Wolters, Ronald E. Savage, Ashlyn Gruber, Marjorie J. Lindhurst, Scott M. Paul, Eva Dombi, Brian Schwartz, Leslie G. Biesecker, Thomas N. Darling, Kim M. Keppler-Noreuil, Jasmine Burton-Akright |
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Jazyk: | angličtina |
Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
Oncology Adult Male medicine.medical_specialty Adolescent Maximum Tolerated Dose AKT1 Aminopyridines Pain Pilot Projects Article Proteus Syndrome 03 medical and health sciences Young Adult 0302 clinical medicine Internal medicine Cerebriform connective tissue nevus Genetics medicine Clinical endpoint Humans Tissue Distribution Phosphorylation Child Nevus Genetics (clinical) Connective tissue nevus business.industry Imidazoles Middle Aged medicine.disease Prognosis Proteus syndrome 030104 developmental biology Pharmacodynamic Study 030220 oncology & carcinogenesis Overgrowth syndrome Pharmacodynamics Female business Proto-Oncogene Proteins c-akt |
Popis: | 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/m(2)/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/m(2)/day of miransertib is an appropriate starting point for future efficacy trials and that this agent shows promise of therapeutic efficacy in children with Proteus syndrome. |
Databáze: | OpenAIRE |
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