Generation and characterization of a mouse model for ALK-positive anaplastic thyroid carcinoma

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Anaplastic thyroid cancer (ATC) is a rare but highly lethal form of thyroid cancer. Median survival is only 6 months. In metastatic ATC, the use of aggressive approaches, e.g. combined radio-/chemotherapy, does not improve survival and new therapeutic strategies are urgently needed. The primary mechanism that promotes development and progression of ATC is overactivation of cellular signaling pathways, especially the PI3K and MAPK pathways, due to oncogenic mutations. Better understanding the molecular pathogenesis of thyroid cancer may open unprecedented opportunities for the development of novel clinical strategies for anaplastic thyroid cancer. Possibly, ATC should not be seen as a uniform disease, but rather be distinguished depending on the driver mutation. For example, mutations in the anaplastic lymphoma kinase (ALK) have been reported in ATC patients and are considered driver mutations. However, this has not yet been proven experimentally. If proven, patients with ALK-positive ATCs could receive targeted therapy with available FDA-approved ALK-inhibitors. Therefore, aim of this project is to establish a mouse model for ALK-positive anaplastic thyroid carcinoma to determine the role of activating ALK mutations in ATC development and progress and to study new treatment options for this ATC subgroup, especially ALK inhibitors. To achieve this aim, we will use a novel conditional knock-in mouse model with thyroid-specific expression of a constitutively active ALK mutant (F1174L). In this mouse model, we will study the development and progress of ALK-positive ATC (dedifferentiation, timing and extent of metastasis) with serial in vivo bioluminescence imaging and thyroid histology. Furthermore, we will study the functional and molecular characteristics of ALK-positive ATC, especially signaling pathway activation, radioiodine uptake, angiogenesis as well as the immunological microenvironment (e.g. PD-L1 expression and density and type of tumor associated macrophages). Major goal of this project is to treat these ATC mice with an ALK inhibitor (TAE-684) to determine if ALK inhibition slows tumor progress and prolongs survival in these mice and, thus, represents a promising treatment option for ALK-positive ATC. These results are of immediate clinical relevance, because successful demonstration of efficacy of ALK inhibitors will change the treatment paradigm for ALK-positive ATC patients. In addition, this project will provide an immunocompetent ATC mouse model to study further innovative treatments, e.g. immunotherapy with checkpoint inhibitors.