Translating current basic research into future therapies for neurofibromatosis type 1

Abstract

Neurofibromatosis type 1 (NF1) is a hereditary tumour syndrome that predisposes to benign and malignant tumours originating from neural crest cells. Biallelic inactivation of the tumour-suppressor gene NF1 in glial cells in the skin, along a nerve plexus or in the brain results in the development of benign tumours: cutaneous neurofibroma, plexiform neurofibroma and glioma, respectively. Despite more than 40 years of research, only one medication was recently approved for treatment of plexiform neurofibroma and no drugs have been specifically approved for the management of other tumours. Work carried out over the past several years indicates that inhibiting different cellular signalling pathways (such as Hippo, Janus kinase/signal transducer and activator of transcription, mitogen-activated protein kinase and those mediated by sex hormones) in tumour cells or targeting cells in the microenvironment (nerve cells, macrophages, mast cells and T cells) might benefit NF1 patients. In this review, we outline previous strategies aimed at targeting these signalling pathways or cells in the microenvironment, agents that are currently in clinical trials, and the latest advances in basic research that could culminate in the development of novel therapeutics for patients with NF1.

Fig. 1. Therapeutic strategies developed and tested in the past.

Overview of previously trialled therapies for the most common types of tumour associated with NF1. Therapeutic agents include the farnesyltransferase inhibitor ipifarnib, inhibitors of receptor tyrosine kinases (RTKs) upstream of RAS (imatinib, sunitinib, sorafenib), inhibitors of components of the pathway downstream of RAS (mTOR inhibitors sirolimus, everolimus) and anti-fibrotic agents such as pirfenidone.

Fig. 2. Current therapeutics strategies under development.

Overview of current therapies under investigation for the most common types of tumour associated with NF1, including inhibitors of receptor tyrosine kinases (RTKs) upstream of RAS (capmatinib), components of the pathway downstream of RAS (MEK inhibitors), immune-checkpoint inhibitors (ipilimumab, nivolumab, pembrolizumab) and BET inhibitors.

Fig. 3. Advances in basic research that could lead to the generation of novel therapeutics.

Overview of the potential future therapies for the most common types of tumour associated with NF1, including targeting the Hippo pathway, JAK/STAT signalling pathway and oestrogen signalling as well as components of the NF1^+/− tumour microenvironment (fibroblasts, nerve cells, macrophages and other immune cells).