LAUSR

Children and young adults with type 1 neurofibromatosis (NF1) are at risk to develop plexiform neurofibromas, which can undergo malignant transformation to malignant peripheral nerve sheath tumors (MPNSTs). MPNSTs are among the most frequently occurring sarcomas in children and young adults and are especially problematic in NF1 patients. Currently, complete surgical excision is the only curative therapy for NF1-associated MPNST, but these tumors are often not completely resectable. Therefore, it is very important to identify promising drugs that can be rapidly moved into clinical trials to improve the therapy of patients with MPNSTs. We have developed a faithful zebrafish model of NF1-associated MPNST by using genome engineering to develop zebrafish lines harboring loss-of-function mutations of the duplicated nf1a and nf1b genes and p53. Our nf1 and p53 deficient zebrafish models develop MPNSTs that are very similar to human NF1-associated MPNST, and thus are ideal for experiments to test the efficacy of FDA-approved small molecule drugs in vivo. To test the FDA-approved drugs for activity against MPNST tumor cells, about 100 Sox10:mCherry expressed MPNST primary tumor cells were transplanted into dechorionized 2 day-post-fertilization (dpf) larval fish using a micro-injector. MPNST-implanted embryos were exposed to individual test compounds added to the fish water at a range of concentrations and to the vehicle control. After 4-days of treatment, quantitative assessment of the remaining mCherry-labeled tumor cell numbers were measured using the ImageJ software for each treated embryo. Currently, trametinib and sunitinib caused marked antitumor effects indicated by reduced numbers of mCherry-labeled nf1-deficient MPNST cells compared to the DMSO control in this study. We are now applying this embryonic implantation assay to identify combinations of FDA-approved drugs that have a high degree of efficacy against MPNST and can be rapidly “repurposed” to improve the treatment of this disease. Citation Format: Dong Hyuk Ki, Shuning He, A. Thomas Look. Drug discovery for NF1-associated malignant peripheral nerve sheath tumors using the zebrafish model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5014. doi:10.1158/1538-7445.AM2017-5014