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Molecular Therapies for Tuberous Sclerosis and Neurofibromatosis

  • Neuro-Oncology (LE Abrey, Section Editor)
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Abstract

Neurofibromatosis type 1 (NF1) and tuberous sclerosis complex (TSC) are autosomal-dominant genetic disorders that result from dysregulation of the PI3K/AKT/mammalian target of rapamycin (mTOR) pathway. NF1 is caused by mutations in the NF1 gene on chromosome 17q11.2. Its protein product, neurofibromin, functions as a tumor suppressor and ultimately produces constitutive upregulation of mTOR. TSC is caused by mutations in either the TSC1 (chromosome 9q34) or TSC2 (chromosome 16p.13.3) genes. Their protein products, hamartin and tuberin, respectively, form a dimer that acts via the GAP protein Rheb (Ras homolog enhanced in brain) to directly inhibit mTOR, again resulting in upregulation. Specific inhibitors of mTOR are in clinical use, including sirolimus, everolimus, temsirolimus, and deforolimus. Everolimus has been shown to reduce the volume and appearance of subependymal giant cell astrocytomas (SEGA), facial angiofibromas, and renal angiomyolipomas associated with TSC, with a recent FDA approval for SEGA not suitable for surgical resection. This article reviews the use of mTOR inhibitors in these diseases, which have the potential to be a disease-modifying therapy in these and other conditions.

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Disclosure

Conflicts of interest: D.N. Franz: has received grant support for study drug and costs for conducting the research described in this paper, Novartis; has received a consulting fee or honorarium for conduct and design of clinical trials, Novartis; has received support for travel costs to meet with regulatory agencies, present research results, design protocols, Novartis; has received support for study medication, administrative support for study conduct, Novartis; has given expert testimony for various plaintiff's and defendant's attorneys; has received payment of travel and lodging expenses for invited lectures, not as part of a speaker's bureau; is on the speaker's bureau for UCB Pharma; B.D. Weiss: none.

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  1. Departments of Pediatrics and Neurology, Tuberous Sclerosis Clinic, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, 45229, USA

    David Neal Franz

  2. Department of Pediatrics, Division of Hematology/Oncology, Neuroblastoma Program, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, 45229, USA

    Brian D. Weiss

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Franz, D.N., Weiss, B.D. Molecular Therapies for Tuberous Sclerosis and Neurofibromatosis. Curr Neurol Neurosci Rep 12, 294–301 (2012). https://doi.org/10.1007/s11910-012-0269-4

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