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Clinical report: one year of treatment of Proteus syndrome with miransertib (ARQ 092)

Authors
  • Biesecker, Leslie G.1
  • Edwards, Matthew2, 3
  • O'Donnell, Sheridan2
  • Doherty, Paula4
  • MacDougall, Thomas5
  • Tith, Kate6
  • Kazakin, Julia6
  • Schwartz, Brian6
  • 1 Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA;
  • 2 Hunter Genetics, Hunter-New England Local Health District, New South Wales Department of Health, Waratah, New South Wales 2298, Australia;
  • 3 Department of Paediatrics, Western Sydney University School of Medicine, Penrith, New South Wales 2751, Australia;
  • 4 Pharmacy, John Hunter Hospital, Hunter-New England Local Health District, New South Wales Department of Health, New South Wales 2310, Australia;
  • 5 Medical Imaging, Paediatric Radiology, Hunter-New England Local Health District, New South Wales Department of Health, New South Wales 2310, Australia;
  • 6 Arqule Inc, Burlington, Massachusetts 01803, USA
Type
Published Article
Journal
Cold Spring Harbor Molecular Case Studies
Publisher
Cold Spring Harbor Laboratory Press
Publication Date
Feb 01, 2020
Volume
6
Issue
1
Identifiers
DOI: 10.1101/mcs.a004549
PMID: 32014856
PMCID: PMC6996520
Source
PubMed Central
Keywords
License
Unknown

Abstract

A 20-yr-old man with Proteus syndrome (PS) and somatic mosaicism of the AKT1 c.49G > A p.(E17K) variant had asymmetric overgrowth of the right frontal and facial bones, asymmetric spinal overgrowth with thoracolumbar scoliosis, dilatation of the inferior vena cava, testicular cystadenoma, bilateral knee deformities, macrodactyly, and apparent intellectual disability. Miransertib (ARQ 092) is an oral, allosteric, selective pan-AKT inhibitor initially developed for cancer therapeutics, now being evaluated for the treatment of PS. After baseline evaluation, the patient started unblinded treatment of 10 mg oral miransertib daily (∼5 mg/m2/day), escalated to 30 mg daily (∼15 mg/m2/day), and then to 50 mg daily (∼25 mg/m2/day) after 3 mo of treatment. Adverse events included dry mouth, one episode of gingivostomatitis, and loose, painful dentition due to preexisting periodontal disease, all of which resolved spontaneously. After 11 mo of treatment, the patient reported improved general well-being, increased mobility of the ankle, spine, and hands, a subjective decrease in size of the right facial bone overgrowth, and reduced areas of cerebriform connective tissue nevi on the soles. Whole-body MRI findings were stable without apparent disease progression. We conclude that 1 yr of treatment with miransertib was beneficial in this case.

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