Abstract 1957: Molecular pathogenesis and drug synergism in a zebrafish model of high risk neuroblastoma

We have developed a transgenic zebrafish model that overexpresses MYCN and harbors loss-of-function mutations of the nf1 tumor suppressor. In this model, loss of nf1 leads to aberrant activation of RAS-MAPK signaling, promoting both increased tumor cell survival and rapid tumor cell proliferation. These neuroblastomas are very aggressive in that almost all of the fish develop neuroblastoma by 3 weeks of age. Three-week old juvenile fish are very small, making it feasible to test the effectiveness of many drugs and drug combinations in vivo for activity against the primary tumors. We demonstrate these advantages of the model by showing marked synergistic anti-tumor effects of a MEK inhibitor (trametinib) and a retinoid (isotretinoin) in vivo at several different dosage combinations by in vivo isobologram analysis. Thus, inhibition of RAS-MAPK signaling can significantly improve the treatment of this very aggressive form of neuroblastoma when it is combined with the inhibition of other key pathways. Because of the very high penetrance and rapid onset of neuroblastoma in our nf1-deficient, MYCN-transgenic zebrafish model, it is one of the only model systems in which extensive analysis of the synergistic activity of two or more drugs can be evaluated in primary tumors in vivo. This capability is especially valuable given that mutations causing RAS-MAPK pathway hyperactivation have been shown to arise frequently at the time of relapse of childhood neuroblastomas, indicating the need to eliminate these mutated tumor cells as a component of the primary treatment. Note: This abstract was not presented at the meeting. Citation Format: Shuning He, Marc R. Mansour, Mark W. Zimmerman, Hillary M. Layden, A. Thomas Look. Molecular pathogenesis and drug synergism in a zebrafish model of high risk neuroblastoma [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 1957. doi:10.1158/1538-7445.AM2017-1957