Abstract PR04: Linking development and cancer modeling in zebrafish identifies putative therapeutic targets in medullary thyroid cancer

Abstract

Abstract Medullary thyroid cancer (MTC) is a neuroendocrine cancer that arises from malignant transformation of calcitonin-producing C-cells. A majority of MTC is associated with somatically acquired mutations in the proto-oncogene Rearranged during transfection (RET), resulting in constitutive activation of downstream effectors of the ERK and AKT signaling pathways. While surgical treatment may be curative in patients with localized MTC, a significant fraction of patients harbor residual disease and ultimately relapse. Much of the research on MTC has converged on inhibition of RET, however, studies suggest that other signaling pathways may contribute to disease. As a result, there is a growing need to identify novel targets for MTC. The zebrafish is well regarded as a model to study of development due its genetic tractability, conservation of pathways and rapid organ development; characteristics that also make it a fitting model to study human cancers. In this study we take advantage of these traits to 1) perform an in vivo chemical screen to identify modulators of C-cell development in zebrafish and 2) develop an in vivo oncogenic RET model in zebrafish to test the putative ‘hits’ from our screen. We hypothesize that the nexus of development and cancer modeling in the zebrafish will lead to therapies of potential use in treating MTC. We screened compounds modulating pathways involved in development, kinase signaling and chromatin modification for their ability to influence C-cell development and found that separate inhibition of the FGF and GSKβ; signaling pathways results in marked down-regulation of markers associated with C-cell differentiation. In parallel, we have introduced human oncogenic RET into an analogous cell type of neural crest origin in zebrafish which results in their early transformation, and are testing the ability of the identified ‘hits’ to suppress transformation of these cells. Our results implicate the FGF and GSKβ; pathways in C-cell development and encourage further investigation of their potential as therapeutic targets for MTC. Moreover, our studies highlight the use of zebrafish as model to identify novel targeted therapies in cancer. This abstract is also presented as Poster B44. Citation Format: Jacques A. Villefranc, Aida Alazar, Yariv Houvras. Linking development and cancer modeling in zebrafish identifies putative therapeutic targets in medullary thyroid cancer. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr PR04.