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Article

Preventative Effect of Mebendazole against Malignancies in Neurofibromatosis 1

1
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
2
Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
*
Authors to whom correspondence should be addressed.
Genes 2020, 11(7), 762; https://doi.org/10.3390/genes11070762
Received: 26 May 2020 / Revised: 28 June 2020 / Accepted: 30 June 2020 / Published: 8 July 2020
(This article belongs to the Special Issue Genomics and Models of Nerve Sheath Tumors)
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. View Full-Text
Keywords: neurofibromatosis 1 (NF1); mebendazole (MBZ); COX-2 inhibitor; MPNST; malignancy; sarcoma; chemoprevention neurofibromatosis 1 (NF1); mebendazole (MBZ); COX-2 inhibitor; MPNST; malignancy; sarcoma; chemoprevention
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MDPI and ACS Style

Staedtke, V.; Gray-Bethke, T.; Riggins, G.J.; Bai, R.-Y. Preventative Effect of Mebendazole against Malignancies in Neurofibromatosis 1. Genes 2020, 11, 762. https://doi.org/10.3390/genes11070762

AMA Style

Staedtke V, Gray-Bethke T, Riggins GJ, Bai R-Y. Preventative Effect of Mebendazole against Malignancies in Neurofibromatosis 1. Genes. 2020; 11(7):762. https://doi.org/10.3390/genes11070762

Chicago/Turabian Style

Staedtke, Verena, Tyler Gray-Bethke, Gregory J. Riggins, and Ren-Yuan Bai. 2020. "Preventative Effect of Mebendazole against Malignancies in Neurofibromatosis 1" Genes 11, no. 7: 762. https://doi.org/10.3390/genes11070762

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