Current status of MEK inhibitors in the treatment of plexiform neurofibromas
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ANNUAL ISSUE PAPER
Current status of MEK inhibitors in the treatment of plexiform neurofibromas Andrea M. Gross 1 & Eva Dombi 1 & Brigitte C. Widemann 1 Received: 2 June 2020 / Accepted: 5 June 2020 # This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2020
Abstract Background Neurofibromatosis type 1 (NF1)-related plexiform neurofibromas (pNF) can be debilitating and until recently, surgery was the only potentially effective therapy for these tumors. Methods We review critical steps in the path towards the FDA approval of the first medical therapy for NF1 pNF and the current status of MEK inhbitor therapy. Results Sustained efforts by the NF community have resulted in a detailed understanding of the natural history and biology of NF1-related peripheral nerve sheath tumors. This work provided the basis for the development of meaningful clinical trials targeting pNF. Inhibition of the RAS/MAPK signaling pathway with MEK inhibitors identified the first medical therapy which resulted in shrinkage in the majority of children with NF1 and large inoperable pNF. Based on this finding and subsequent demonstration of clinical benefit, the MEK inhibitor selumetinib recently received approval by the United States Food and Drug Administration (FDA) for children with symptomatic pNF. Conclusions Sustained efforts and collaborations have resulted in identification of MEK inhibitors as effective therapy for NF1 pNF. Future work work will be directed at prevention of pNF morbidity and deepening the reponse in symptomatic pNF. Keywords Trial design . Neurofibromatosis 1 . Plexiform neurofibroma . MEK inhibitor . Clinical trial
Background Neurofibromatosis type 1 and peripheral nerve sheath tumors NF1 is the most frequently inherited single-gene disorder of the nervous system (incidence 1:3000) [1, 2] and is characterized by the development of progressive benign and malignant tumors of the central and peripheral nervous system, as well as a variety of non-tumor manifestations. The protein product of the NF1 gene, neurofibromin, regulates Ras activity through its GTPase-related domain. Lack of functional neurofibromin leads to hyperactive Ras and the initiation of a cascade of signaling events such as activation of Raf and MAPK that lead to increased cell proliferation and tumorigenesis [3, 4].
* Brigitte C. Widemann [email protected] 1
Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, 10 Center Drive, Building 10, Room 1-3752, Bethesda, MD 20892, USA
People with NF1 can develop different types of peripheral nerve sheath tumors (PNST). Almost all individuals with NF1 develop cutaneous neurofibromas (cNF), characterized by biallelic loss of NF1, which never transform into malignancy. Up to 50% of individuals with NF1 develop plexiform neurofibromas (pNF), which are histologically benign but can cause substantial morbidity [5–8] and can transform to malignant peripheral nerve sheath tumors (MPNST), aggressive sarcomas which carry
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