Abstract
Patients with RASopathy Neurofibromatosis 1 (NF1) are at a markedly increased risk of the development of benign and malignant tumors. Malignant tumors are often recalcitrant to treatments and associated with poor survival; however, no chemopreventative strategies currently exist. We thus evaluated the effect of mebendazole, alone or in combination with cyclooxygenase-2 (COX-2) inhibitors, on the prevention of NF1-related malignancies in a cis Nf1+/−;Tp53+/− (NPcis) mouse model of NF1. Our in vitro findings showed that mebendazole (MBZ) inhibits the growth of NF1-related malignant peripheral nerve sheath tumors (MPNSTs) through a reduction in activated guanosine triphosphate (GTP)-bound Ras. The daily MBZ treatment of NPcis mice dosed at 195 mg/kg daily, initiated 60 days after birth, substantially delayed the formation of solid malignancies and increased median survival (p < 0.0001). Compared to placebo-treated mice, phosphorylated extracellular signal-regulated kinase (pERK) levels were decreased in the malignancies of MBZ-treated mice. The combination of MBZ with COX-2 inhibitor celecoxib (CXB) further enhanced the chemopreventative effect in female mice beyond each drug alone. These findings demonstrate the feasibility of a prevention strategy for malignancy development in high-risk NF1 individuals.
Highlights
RASopathy Neurofibromatosis 1 (NF1) is an autosomal dominant hereditary cancer predisposition syndrome that affects ~1:3000 individuals [1]
Human malignant peripheral nerve sheath tumors (MPNSTs) cells NF90-8 and sNF96.2, both derived from NF1 patients, were treated with cells NF90-8 and sNF96.2, both derived fromICNF1 patients, were treated
VEGFR2 autophosphorylation [17,18], which was corroborated by other investigators, applied to formation and VEGFR2 autophosphorylation [17,18], which was corroborated by other investigators, various preclinical cancer models and translated into clinical trials for adult and pediatric applied to various preclinical cancer models and translated into clinical trials for adult and patients with cancer (NCT03925662, NCT03628079, NCT02644291, NCT01729260, NCT01837862)
Summary
RASopathy Neurofibromatosis 1 (NF1) is an autosomal dominant hereditary cancer predisposition syndrome that affects ~1:3000 individuals [1]. It is caused by mutations in the neurofibromin 1 (Nf1). Patients with NF1 have an increased cancer risk and mortality, and lower survival compared with the general population [3,4]. Based on the Finnish NF1 Registry, the estimated lifetime cancer risk in patients with NF1 is 59.6%, with an estimated cumulative cancer risk of ~25% and ~39% by age 30 and 50 years, whereas the respective percentages in the general Finnish population are much lower, at 30.8%, 0.8% and 3.9% [3]. Other malignancies include breast cancer, rhabdomyosarcomas, pheochromocytoma, gastrointestinal stromal tumor (GIST), malignant fibrous histiocytoma, and thyroid cancer [3]
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