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Neuropediatrics 2019; 50(05): 300-303
DOI: 10.1055/s-0039-1691830
Short Communication
Georg Thieme Verlag KG Stuttgart · New York

Trametinib Induces Neurofibroma Shrinkage and Enables Surgery

Pia Vaassen
1   Department of Pediatrics, Sana Kliniken Duisburg, Germany
,
Nikola Dürr
2   Department of Radiology and Neuroradiology, Sana Kliniken Duisburg, Germany
,
Andreas Röhrig
3   Department of Pediatric Neurosurgery, Asklepios Klinik St. Augustin, Germany
,
Rainer Willing
4   Department of Pediatrics, Ubbo-Emmius-Klinik Aurich, Germany
,
Thorsten Rosenbaum
1   Department of Pediatrics, Sana Kliniken Duisburg, Germany
› Author Affiliations
Further Information

Publication History

07 March 2019

23 April 2019

Publication Date:
29 May 2019 (online)

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Abstract

Plexiform neurofibromas are congenital peripheral nerve sheath tumors characteristic of neurofibromatosis type 1 (NF1)—a frequent neurocutaneous disorder caused by mutations of the NF1 tumor suppressor gene. Since plexiform neurofibromas are a major cause of the burden of disease and may also progress to malignancy, many efforts have been undertaken to find a cure for these tumors. However, neither surgery nor medication has so far produced a breakthrough therapeutic success. Recently, a clinical phase I study reported significant shrinkage of plexiform neurofibromas following treatment with the MEK inhibitor selumetinib. Here, we report an 11-year-old NF1 patient with a large plexiform neurofibroma of the neck that had led to a sharp-angled kinking of the cervical spine and subsequent myelopathy. Although surgical stabilization of the cervical vertebral column was urgently recommended, the vertebral column was inaccessible due to extensive tumor growth. In this situation, treatment with the MEK inhibitor trametinib was initiated which resulted in a 22% reduction in tumor volume after 6 months of therapy and finally enabled surgery. These data show that MEK inhibitors may not lead to complete disappearance of NF1-associated plexiform neurofibromas but can be an essential step in a multimodal therapeutic approach for these tumors. The course of our patient suggests that MEK inhibitors are likely to play a significant role in providing a cure for one of the most devastating manifestations of NF1.

Keywords

plexiform neurofibroma - neurofibromatosis type 1 - MEK inhibitor - trametinib - tuberous sclerosis - everolimus
 

  • References

  • 1 Neurofibromatosis: Phenotype, Natural History, and Pathogenesis. 3rd ed. Baltimore, MD: The John Hopkin’s University Press; 1999
    Search in Google Scholar
  • 2 Serra E, Rosenbaum T, Winner U. , et al. Schwann cells harbor the somatic NF1 mutation in neurofibromas: evidence of two different Schwann cell subpopulations. Hum Mol Genet 2000; 9 (20) 3055-3064
    CrossrefPubMedSearch in Google Scholar
  • 3 Chen Z, Mo J, Brosseau JP. , et al. Spatiotemporal loss of NF1 in Schwann cell lineage leads to different types of cutaneous neurofibroma susceptible to modification by the hippo pathway. Cancer Discov 2019; 9 (01) 114-129
    CrossrefPubMedSearch in Google Scholar
  • 4 Meany H, Widemann BC, Ratner N. Malignant peripheral nerve sheath tumors: Prognostic and diagnostic markers and therapeutic targets. In: Upadhyaya M, Cooper DN. , eds. Neurofibromatosis Type 1. Molecular and Cellular Biology. Berlin: Springer; 2012: 445-467
    Search in Google Scholar
  • 5 Jessen WJ, Miller SJ, Jousma E. , et al. MEK inhibition exhibits efficacy in human and mouse neurofibromatosis tumors. J Clin Invest 2013; 123 (01) 340-347
    CrossrefPubMedSearch in Google Scholar
  • 6 Dombi E, Baldwin A, Marcus LJ. , et al. Activity of selumetinib in neurofibromatosis type 1-related plexiform neurofibromas. N Engl J Med 2016; 375 (26) 2550-2560
    CrossrefPubMedSearch in Google Scholar
  • 7 Purandare SM, Lanyon WG, Connor JM. Characterisation of inherited and sporadic mutations in neurofibromatosis type-1. Hum Mol Genet 1994; 3 (07) 1109-1115
    CrossrefPubMedSearch in Google Scholar
  • 8 Combemale P, Valeyrie-Allanore L, Giammarile F. , et al. Utility of 18F-FDG PET with a semi-quantitative index in the detection of sarcomatous transformation in patients with neurofibromatosis type 1. PLoS One 2014; 9 (02) e85954
    CrossrefPubMedSearch in Google Scholar
  • 9 McCowage G, Mueller S, Pratilas C. , et al. Trametinib in pediatric patients with neurofibromatosis type 1 (NF-1)-associated plexiform neurofibroma: a phase I/IIa study. J Clin Oncol 2018; 36 (15_suppl): 10504
    CrossrefPubMedSearch in Google Scholar
  • 10 Welsh SJ, Corrie PG. Management of BRAF and MEK inhibitor toxicities in patients with metastatic melanoma. Ther Adv Med Oncol 2015; 7 (02) 122-136
    CrossrefPubMedSearch in Google Scholar
  • 11 Dombi E, Solomon J, Gillespie AJ. , et al. NF1 plexiform neurofibroma growth rate by volumetric MRI: relationship to age and body weight. Neurology 2007; 68 (09) 643-647
    CrossrefPubMedSearch in Google Scholar
  • 12 Gross AM, Wolters P, Baldwin A. , et al. SPRINT: Phase II study of the MEK 1/2 inhibitor selumetinib (AZD6244, ARRY-142886) in children with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PN). J Clin Oncol 2018; 36 (15_suppl): 10503
    CrossrefPubMedSearch in Google Scholar
  • 13 Papalia H, Audic F, Rivière GR, Verschuur A, André N. Quick and sustained clinical response to MEK inhibitor I in a NF1 patient with neurofibromas. Ecancermedicalscience 2018; 12: 862
    Search in Google Scholar
  • 14 Knight T, Shatara M, Carvalho L, Altinok D, Poulik J, Wang ZJ. Dramatic response to trametinib in a male child with neurofibromatosis type 1 and refractory astrocytoma. Pediatr Blood Cancer 2019; 66 (01) e27474
    CrossrefPubMedSearch in Google Scholar
  • 15 Franz DN, Capal JK. mTOR inhibitors in the pharmacologic management of tuberous sclerosis complex and their potential role in other rare neurodevelopmental disorders. Orphanet J Rare Dis 2017; 12 (01) 51-60
    CrossrefPubMedSearch in Google Scholar