Neurofibromatosis type 1-associated optic pathway gliomas: pathogenesis and emerging treatments

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder associated with an increased risk of developing a variety of benign and malignant tumors. Fifteen to 20% of children with NF1 are diagnosed with an optic pathway glioma (NF1-OPG) before 7 years of age, and more than half of them experience visual decline. At present, no effective therapy is available for prevention, restoration, or even stabilization of vision loss in subjects affected by NF1-OPG. This paper aims to review the main emerging pharmacological approaches that have been recently assessed in preclinical and clinical settings. We performed a search of the literature using Embase, PubMed, and Scopus databases to identify articles regarding NF1-OPGs and their treatment up to July 1st, 2022. The reference lists of the analyzed articles were also considered a source of literature information. To search and analyze all relevant English articles, the following keywords were used in various combinations: neurofibromatosis type 1, optic pathway glioma, chemotherapy, precision medicine, MEK inhibitors, VEGF, nerve growth factor. Over the past decade, basic research and the development of genetically engineered mice models of NF1-associated OPG have shed light on the cellular and molecular mechanisms underlying the disease and inspired animal and human testing of several compounds. A promising line of research is focusing on the inhibition of mTOR, a protein kinase controlling proliferation, protein synthesis rate and cell motility that is highly expressed in neoplastic cells. Several mTOR blockers have been tested in clinical trials, the most recent of which employed oral everolimus with encouraging results. A different strategy aims at restoring cAMP levels in neoplastic astrocytes and non-neoplastic neurons, since reduced intracellular cAMP levels contribute to OPG growth and, more importantly, are the major determinant of NF1-OPG-associated visual decline. So far, however, this approach has only been attempted in preclinical studies. Stroma-directed molecular therapies - seeking to target Nf1 heterozygous brain microglia and retinal ganglion cells (RGCs) - are another fascinating field. Microglia-inhibiting strategies have not yet reached clinical trials, but preclinical studies conducted over the last 15 years have provided convincing clues of their potential. The importance of NF1-mutant RGCs in the formation and progression of OPGs also holds promise for clinical translation. The evidence of Vascular Endothelial Growth Factor (VEGF)-Vascular Endothelial Growth Factor (VEGFR) signaling hyperactivity in pediatric low-grade gliomas prompted the use of bevacizumab, an anti-VEGF monoclonal antibody, which was tested in children with low-grade gliomas or OPGs with good clinical results. Neuroprotective agents have also been proposed to preserve and restore RGCs and topical eye administration of nerve growth factor (NGF) has demonstrated encouraging electrophysiological and clinical results in a double-blind, placebo-controlled study. Traditional chemotherapy in patients with NF1-OPGs does not significantly ameliorate visual function, and its effectiveness in halting tumor growth cannot be considered a satisfactory result. Newer lines of research should be pursued with the goal of stabilizing or improving the vision, rather than reducing tumor volume. The growing understanding of the unique cellular and molecular characteristics of NF1-OPG, coupled with the recent publication of promising clinical studies, raise hope for a shift towards precision medicine and targeted therapies as a first-line treatment.