*Article* **Preventative E** ff**ect of Mebendazole against Malignancies in Neurofibromatosis 1**

#### **Verena Staedtke 1,\*, Tyler Gray-Bethke 1, Gregory J. Riggins 2 and Ren-Yuan Bai 2,\***


Received: 26 May 2020; Accepted: 30 June 2020; Published: 8 July 2020

**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 e ffect 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 e ffect in female mice beyond each drug alone. These findings demonstrate the feasibility of a prevention strategy for malignancy development in high-risk NF1 individuals.

**Keywords:** neurofibromatosis 1 (NF1); mebendazole (MBZ); COX-2 inhibitor; MPNST; malignancy; sarcoma; chemoprevention
