What are the emerging treatments for neurofibromatosis?

Neurofibromatosis (NF) is one of the major neurocutaneous disorders neurologists see. These are disorders which primarily affect the nervous system and have prominent skin manifestations. Also known as phakomatoses, they are typified by abnormal growths and a variety of cancers. They include well-defined conditions such as tuberous sclerosis complex (TSC), Sturge-Weber syndrome (SWS), von Hipple Lindau disease (VHL), schwannomatosis, and the various PTEN hamartoma tumour syndromes. There are two types of neurofibromatosis, NF1 and NF2. NF2 is characterised by vestibular schwannomas, tumours arising from the sheath that encases the nerve that control balance, and by meningiomas, tumours of the covering of the brain.

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NF1, also known as von Recklinghausen disease is, by far, the commoner form of neurofibromatosis. It is readily recognised on the skin by the frequently multiple and disfiguring nerve tumours called neurofibromas. Other benign skin lesions include the coffee-coloured skin lesions aptly called cafe-au-lait spots, armpit lesions called axillary freckles, and small lesions on the iris of the eyes called Lisch nodules. More sinister skin lesions called malignant peripheral nerve sheath tumours (MPNST) are, as the name implies, capable of spreading to other organs such as the lungs. Other sinister tumours in NF1 include gliomas of the brain and optic nerve, gastrointestinal stromal tumours (GIST) of the gut, and rhabdomyosarcomas of bone.

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What can neurologists do for people with neurofibromatosis? Traditionally, nothing much apart from watchful waiting. We would monitor for the development of tumours by regular surveillance MRI scans of the brain and spine, and refer people with painful, compressive, or malignant lesions to the plastic surgeons or neurosurgeons to do what they do best, taking things out. Surgery may work fine for simple neurofibromas, but it is less practical for the complex or plexiform type. Thankfully, many neuroscientists are working hard, looking at different approaches to managing neurofibromas. To illustrate, below are 5 emerging treatments for neurofibromatosis. 

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In a 2016 paper in the New England Journal of Medicine, Eva Dombi and colleagues investigated the effect of selumetinib, an oral inhibitor of an enzyme called MAPK kinase (MEK) in 24 children with NF1. The paper, titled Activity of selumetinib in neurofibromatosis type 1-related plexiform neurofibromas, showed that selumetinib reduced the size of neurofibromas, and there was evidence that it improved pain and reduced disfigurement.

By Dimitrios MalamosOwn work, CC BY 4.0, Link


In a 2012 paper published in Lancet Oncology, Kent Robertson and colleagues, investigated the potential benefit of Imitanib, an inhibitor of the enzyme tyrosine kinase, in 36 people with NF1. The paper, titled Imitatinib mesylate for plexiform neurofibromas in patients with neurofibromatosis type 1: a phase 2 trial, showed at least a 20% reduction in one or more plexiform neurofibromas.

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Brian Weiss and colleagues investigated the effect of sirolimus, an inhibitor of mTOR complex 1, in 46 people with NF1 and published their findings in the journal Neuro-Onclology. The paper, titled Sirolimus for progressive neurofibromatosis type 1-associated plexiform neurofibromas, demonstrated that sirolimus prolonged the time to progression (TTP) of plexiform neurofibromas by about 4 months. A modest effect they admit, but nevertheless, a hope-raising effect.

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Everolimus is already making waves in the treatment of various lesions in tuberous sclerosis complex, and it is not surprising that it has turned up here. In their paper titled Treatment of disfiguring cutaneous lesions in neurofibromatosis-1 with everolimus, published in the journal Drugs in R&D, John Slopis and colleagues reported that everolimus significantly reduced the surface volume of NF1 lesions, including plexiform neurofibromas. The authors were however cautious, calling for future studies to confirm these results. Unfortunately, one such study in the Journal of Investigational Dermatology poured cold water on the reported benefit of everolimus. The paper was titled Absence of Efficacy of Everolimus in Neurofibromatosis 1-Related Plexiform Neurofibromas: Results from a Phase 2a Trial. Hopefully future studies will be more favourable!

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Pegylated interferon alfa-2b

Regina Jakacki and colleagues looked at the effect of pegylated interferon alfa-2b on plexiform neurofibromas and found a greater than doubling of their time to progression (TTP). Their paper is published in Neuro-Oncology, and it is titled Phase II trial of pegylated interferon alfa-2b in young patients with neurofibromatosis type 1 and unresectable plexiform neurofibromas. As the authors studied a reasonable number of subjects, 84, and as the trial was placebo-controlled trial, this result is unlikely to be overturned by future trials…but only time will tell.

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Therefore is clearly enough justification for hope in the search for a cure for neurofibromatosis.