Abstract
The neurofibromatosis syndromes, including NF1, NF2, and schwannomatosis, are tumor suppressor syndromes characterized by multiple nervous system tumors, particularly Schwann cell neoplasms. NF-related tumors are mainly treated by surgery, and some of them have been treated by but are refractory to conventional chemotherapy. Recent advances in molecular genetics and genomics alongside the development of multiple animal models have provided a better understanding of NF tumor biology and facilitated target identification and therapeutic evaluation. Many targeted therapies have been evaluated in preclinical models and patients with limited success. One major advance is the FDA approval of the MEK inhibitor selumetinib for the treatment of NF1-associated plexiform neurofibroma. Due to their anti-neoplastic, antioxidant, and anti-inflammatory properties, selected natural compounds could be useful as a primary therapy or as an adjuvant therapy prior to or following surgery and/or radiation for patients with tumor predisposition syndromes, as patients often take them as dietary supplements and for health enhancement purposes. Here we review the natural compounds that have been evaluated in NF models. Some have demonstrated potent anti-tumor effects and may become viable treatments in the future.
Highlights
Specialty section: This article was submitted to Cancer Molecular Targets and Therapeutics, a section of the journal Frontiers in Oncology
As a group of slowly progressive autosomal-dominant syndromes, NF is classified into neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis [1]
First presenting with hyperpigmentation-like café-au-lait macules and freckling in afflicted patients, the hallmark of NF1 is the development of neurofibromas, benign tumors composed of an admixture of dysplastic Schwann cells and stromal cells, including fibroblasts, mast cells, and perineural cells embedded in a collagenous extracellular matrix (ECM)
Summary
NF1, previously known as von Recklinghausen disease, affects ~1 in 3,000 individuals [2] and is caused by mutations of the NF1 gene on chromosome 17q11.2 [3,4,5]. Up to 60% of NF2 patients develop meningiomas, mostly benign and often multiple, which are associated with disease severity and increased mortality [21] These tumors cause significant morbidity, including cranial nerve palsy, seizures, and brainstem compression, which may lead to paralysis, aspiration pneumonia, and death. Meningiomas are unresponsive to bevacizumab [24] Another targeted drug, the kinase inhibitor brigatinib, is currently in a phase 2 clinical trial for NF2-related tumors (ClinicalTrials.gov Identifier: NCT04374305). It should be emphasized that NF1-, NF2-, and schwannomatosis-related tumors have distinct genetic origins, they share downstream activation of several molecular targets [1, 2, 6, 16, 25, 52] These deregulated signaling pathways due to tumor suppressor loss in NF-associated tumors provide several targets for therapeutic development
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