Endocrine Abstracts

Anaplastic thyroid cancer (ATC) is the most aggressive thyroid cancer with a median survival of about 6 months. So far, no therapies offering a survival benefit are established. Thus, new therapeutic approaches are urgently needed. In general, genetic alterations leading to ATC increase PI3K and MAPK/ERK signaling and include mutations in receptor tyrosine kinases and tumor suppressor genes. They often occur together with the loss of P53, the most prevalent mutation in human ATC. Among such mutations are mutations and rearrangements of the anaplastic lymphoma kinase (ALK) gene. To study ATC and potential treatment options, we generated a mouse model with inducible thyrocyte-specific expression of constitutively active mutant ALK^F1174L and homozygous deletion of TP53 due to a Cre recombinase under control of the thyroglobulin promoter (TgCreER^T2+/0; ALK^F1174L;Trp53^-/- mice, here referred to as TP53^KO/ALK^F1174L mice). Fifty days after birth, thyrocyte-specific ALK^F1174L expression and TP53 knockout was induced by i.p. injection of tamoxifen. Median survival of TP53^KO/ALK^F1174L mice was severely reduced (105 d) and the mice showed massively enlarged thyroids. Histopathology confirmed development of ATC. To investigate the effects of pharmacologic inhibition with ALK inhibitor TAE-684 in vitro, we established a primary cell line from an advanced TP53^KO/ALK^F1174L mouse thyroid cancer. These cells were injected s.c. into wildtype mice and the resulting tumor was again an ATC, confirming the ATC origin of the cell line. Treatment of these ATC cells with the ALK inhibitor TAE-684 decreased AKT and ERK phosphorylation and induced cytotoxicity in a dose-dependent manner, demonstrating a therapeutic effect. We therefore treated TP53^KO/ALK^F1174L mice with TAE-684 for 30 days, which significantly extended median survival of the treatment group compared to the solvent group (66 days vs. 18 days, P<0.0001). From these data we conclude that patients with ALK-positive ATCs would benefit from ALK inhibitor treatment, e.g. with crizotinib. However, as treatment efficacy ultimately is limited, second-line treatments need to be investigated. The TP53^KO/ALK^F1174L mouse model and the derived cell lines will serve as tools to explore the molecular characteristics of ATCs, especially signaling pathway activation and tumor microenvironment, and to test novel therapeutics for the treatment of advanced thyroid cancers in vitro and in vivo.