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.
Original language | English (US) |
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Article number | 762 |
Pages (from-to) | 1-13 |
Number of pages | 13 |
Journal | Genes |
Volume | 11 |
Issue number | 7 |
DOIs | |
State | Published - Jul 2020 |
Keywords
- COX-2 inhibitor
- Chemoprevention
- MPNST
- Malignancy
- Mebendazole (MBZ)
- Neurofibromatosis 1 (NF1)
- Sarcoma
ASJC Scopus subject areas
- Genetics
- Genetics(clinical)