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Case report: five-year experience of AKT inhibition with miransertib (MK-7075) in an individual with Proteus syndrome

Proteus syndrome is a rare overgrowth disorder caused by postzygotic activating variants in AKT1. Individuals may develop a range of skin, bone, and soft tissue overgrowth leading to functional impairment and disfigurement. Therapy for this disorder is limited to supportive care and surgical interve...

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Autores principales: Ours, Christopher A., Sapp, Julie C., Hodges, Mia B., de Moya, Allison J., Biesecker, Leslie G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8751418/
https://www.ncbi.nlm.nih.gov/pubmed/34649967
http://dx.doi.org/10.1101/mcs.a006134
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author Ours, Christopher A.
Sapp, Julie C.
Hodges, Mia B.
de Moya, Allison J.
Biesecker, Leslie G.
author_facet Ours, Christopher A.
Sapp, Julie C.
Hodges, Mia B.
de Moya, Allison J.
Biesecker, Leslie G.
author_sort Ours, Christopher A.
collection PubMed
description Proteus syndrome is a rare overgrowth disorder caused by postzygotic activating variants in AKT1. Individuals may develop a range of skin, bone, and soft tissue overgrowth leading to functional impairment and disfigurement. Therapy for this disorder is limited to supportive care and surgical intervention. Inhibitors of AKT, originally designed as cancer therapeutics, are a rational, targeted pharmacologic strategy to mitigate the devastating morbidity of Proteus syndrome. We present the 5-yr follow-up of an 18-yr-old male with Proteus syndrome treated with miransertib (MK-7075), an oral pan-AKT inhibitor. At completion of a planned 48-wk phase 1 pharmacodynamic study, the individual derived sufficient benefit that the study was amended to permit continued use and assess the long-term safety of miransertib. The treatment has been well-tolerated with mild treatment-attributed side effects including headache, transient hyperglycemia, and transient elevations of aspartate aminotransferase, alanine aminotransferase, and bilirubin. The patient has experienced sustained improvement of pain and slowed growth of bilateral plantar cerebriform connective tissue nevi. This case report supplements the data from our prior study extending those findings out to 5 years. It shows that at the doses used, miransertib has a favorable safety profile and durable benefit of improving symptoms of pain and slowing progression of overgrowth in Proteus syndrome in a single individual. Although an uncontrolled single report cannot prove safety or efficacy, these data lend support to the encouraging preliminary data of our prior phase 1 pharmacodynamic study.
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spelling pubmed-87514182022-01-20 Case report: five-year experience of AKT inhibition with miransertib (MK-7075) in an individual with Proteus syndrome Ours, Christopher A. Sapp, Julie C. Hodges, Mia B. de Moya, Allison J. Biesecker, Leslie G. Cold Spring Harb Mol Case Stud Research Report Proteus syndrome is a rare overgrowth disorder caused by postzygotic activating variants in AKT1. Individuals may develop a range of skin, bone, and soft tissue overgrowth leading to functional impairment and disfigurement. Therapy for this disorder is limited to supportive care and surgical intervention. Inhibitors of AKT, originally designed as cancer therapeutics, are a rational, targeted pharmacologic strategy to mitigate the devastating morbidity of Proteus syndrome. We present the 5-yr follow-up of an 18-yr-old male with Proteus syndrome treated with miransertib (MK-7075), an oral pan-AKT inhibitor. At completion of a planned 48-wk phase 1 pharmacodynamic study, the individual derived sufficient benefit that the study was amended to permit continued use and assess the long-term safety of miransertib. The treatment has been well-tolerated with mild treatment-attributed side effects including headache, transient hyperglycemia, and transient elevations of aspartate aminotransferase, alanine aminotransferase, and bilirubin. The patient has experienced sustained improvement of pain and slowed growth of bilateral plantar cerebriform connective tissue nevi. This case report supplements the data from our prior study extending those findings out to 5 years. It shows that at the doses used, miransertib has a favorable safety profile and durable benefit of improving symptoms of pain and slowing progression of overgrowth in Proteus syndrome in a single individual. Although an uncontrolled single report cannot prove safety or efficacy, these data lend support to the encouraging preliminary data of our prior phase 1 pharmacodynamic study. Cold Spring Harbor Laboratory Press 2021-12 /pmc/articles/PMC8751418/ /pubmed/34649967 http://dx.doi.org/10.1101/mcs.a006134 Text en © 2021 Ours et al.; Published by Cold Spring Harbor Laboratory Press https://creativecommons.org/licenses/by-nc/4.0/This is a work of the US Government.
spellingShingle Research Report
Ours, Christopher A.
Sapp, Julie C.
Hodges, Mia B.
de Moya, Allison J.
Biesecker, Leslie G.
Case report: five-year experience of AKT inhibition with miransertib (MK-7075) in an individual with Proteus syndrome
title Case report: five-year experience of AKT inhibition with miransertib (MK-7075) in an individual with Proteus syndrome
title_full Case report: five-year experience of AKT inhibition with miransertib (MK-7075) in an individual with Proteus syndrome
title_fullStr Case report: five-year experience of AKT inhibition with miransertib (MK-7075) in an individual with Proteus syndrome
title_full_unstemmed Case report: five-year experience of AKT inhibition with miransertib (MK-7075) in an individual with Proteus syndrome
title_short Case report: five-year experience of AKT inhibition with miransertib (MK-7075) in an individual with Proteus syndrome
title_sort case report: five-year experience of akt inhibition with miransertib (mk-7075) in an individual with proteus syndrome
topic Research Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8751418/
https://www.ncbi.nlm.nih.gov/pubmed/34649967
http://dx.doi.org/10.1101/mcs.a006134
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