Abstract LB-030: Building personalized genetic models of human cancer in zebrafish to predict response to therapy and characterize disease mechanisms

Abstract

Abstract A key challenge posed by personalized medicine is the ability to functionally characterize specific mutations identified in human tumors in order to guide treatment decisions. Transgenic approaches in zebrafish offer an opportunity to model individual patient tumors in order to develop personalized models. To test this concept, we performed a genetic characterization of a patient with thyroid carcinoma and created an in vivo personalized thyroid cancer model in zebrafish. Our studies suggest that this approach can be used to build preclinical models suitable for chemical-genetic studies. Chromosomal rearrangements in RET often lead to chimeric in-frame fusions of its kinase domain with one of several partners, resulting in ectopic, ligand-independent activation of RET. RET/PTC1 encodes a CCDC6-RET fusion and results in ectopic transcriptional activation of RET in thyrocytes and is associated with papillary thyroid cancer (PTC). Cabozantinib, a selective RET inhibitor, restricts growth of RET/PTC1 cell lines and shows marked activity in patients with RET-mutant medullary thyroid cancer. However, its efficacy is limited due unknown mechanisms of resistance. Genetic analysis of the index patient's tumor revealed a RET/PTC1 rearrangement, alterations in the TERT promoter and a focal loss of TP53. We performed molecular analyses of the index patient at distinct points throughout disease to generate a genomic timeline of disease and identify putative landmarks and molecular subtypes of disease. To functionally assess genetic alterations in the index patient, we transiently expressed RET/PTC1 in zebrafish thyroid follicular cells using a zebrafish thyroglobulin promoter. We observed tumor growth by 14 days post fertilization (dpf) in transgenic larvae, with histopathologic characteristics consistent with PTC. A transcriptional profile of RET/PTC1 transgenic zebrafish tumors revealed a set of genes associated with thyrocyte differentiation, as well as transcriptional signatures associated with cell proliferation and cAMP signaling in human thyrocytes. Ex vivo treatment of zebrafish RET/PTC1 tumors with cabozantinib, blocks RET activation and downstream signaling. As a whole, these studies provide proof-of-concept data to develop a transgenic zebrafish platform for patient specific models of thyroid carcinoma and other solid tumors. Citation Format: Jacques A. Villefranc, Chantal Pauli, Viviana Anelli, Sagar Chhangawala, Rohan Bareja, Theresa Scognamiglio, Andrea Sboner, Mark A. Rubin, Yariv Houvras. Building personalized genetic models of human cancer in zebrafish to predict response to therapy and characterize disease mechanisms. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-030.