Emerging therapeutic targets for neurofibromatosis type 1

ABSTRACT

Introduction: Neurofibromatosis type 1 (NF1) is an autosomal dominantly inherited tumor predisposition syndrome with an incidence of one in 3000–4000 individuals with no currently effective therapies. The NF1 gene encodes neurofibromin, which functions as a negative regulator of RAS. NF1 is a chronic multisystem disorder affecting many different tissues. Due to cell-specific complexities of RAS signaling, therapeutic approaches for NF1 will likely have to focus on a particular tissue and manifestation of the disease.

Areas covered: We discuss the multisystem nature of NF1 and the signaling pathways affected due to neurofibromin deficiency. We explore the cell-/tissue-specific molecular and cellular consequences of aberrant RAS signaling in NF1 and speculate on their potential as therapeutic targets for the disease. We discuss recent genomic, transcriptomic, and proteomic studies combined with molecular, cellular, and biochemical analyses which have identified several targets for specific NF1 manifestations. We also consider the possibility of patient-specific gene therapy approaches for NF1.

Expert opinion: The emergence of NF1 genotype–phenotype correlations, characterization of cell-specific signaling pathways affected in NF1, identification of novel biomarkers, and the development of sophisticated animal models accurately reflecting human pathology will continue to provide opportunities to develop therapeutic approaches to combat this multisystem disorder.

KEYWORDS:

• Neurofibromas
• neurofibromatosis type 1
• peripheral nerve sheath tumors
• RAS-MEK-ERK signaling
• RASopathies

Article Highlights

• NF1 is a multisystem disorder with marked variation in clinical variation resulting from mutations in the tumor suppressor NF1 gene. Neurofibromin, the NF1 gene product regulates RAS signaling and its downstream effectors. Currently, there is no effective treatment for this disorder.

• Challenges for devising therapies for NF1 require focusing on both the acute and chronic aspects of this disorder. High-throughput animal and human-derived genomic, transcriptomic, proteomic, and methylome studies combined with molecular, cellular, and biochemical analyses of signaling pathways have identified several therapeutic targets for tumor and non-tumor manifestations of NF1.

• The cellular pathways affected in NF1 tumors and their downstream effects continue to be elucidated. A great deal of evidence indicates that multiple pathways function cooperatively in tumor formation. Many of the therapeutic strategies currently being tested for NF1 involve inhibiting the RAS/MEK and AKT/mTORC1 pathways.

• The most commonly employed therapeutics for these targets are repurposed agents used against cancer (clinicaltrials.gov, clinicaltrialsregister.eu). These drugs have been tested in targeted NF1 animal models and then implemented into clinical trials. Novel therapeutics are also being developed based upon unique aspects of NF1 pathology.

• The drugs primarily used for NF1 treatment are signal transduction inhibitors including RTK, RAS, RAF, MEK, ERK, mTOR, and PI3K inhibitors. Angiogenesis inhibitors and apoptosis inducers are also used. Potential new treatments include restoring neurofibromin function by replacing the NF1 gene, suppression of nonsense mutations, genome editing, and targeted immunotherapy.

• The continuing development of novel cell and animal disease models, induced pluripotent stem cells, and biomarkers will greatly aid both the understanding of basic NF1 biology as well as providing tools for screening novel therapeutics.

This box summarizes key points contained in the article.

Acknowledgments

Figures created using elements from Servier Medical Art according to a Creative Commons Attribution 3.0 Unported License. The authors thank Dr. Andre Bernards for critical reading of the manuscript and for helpful discussions and Brittany Leger for help with figures.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This work was funded by the National Institute of Health (NIH R21 NS096402-01A1), the Department of Defense (W81XWH-16-1-0220), the Neurofibromatosis Therapeutic Acceleration Program (NTAP), the Kanter family and Ian Owen funds.