Preclinical characterization of tyrosine kinase inhibitor-based targeted therapies for neuroendocrine thyroid cancer.

Karine Pozo,Sarah C Oltmann,Keisuke Ishimatsu,Roswitha Pfragner,Masaya Takahashi,Stefan Zahler,Junya Fujimoto,Shuaijun Wang,Chunfeng Tan,James A Bibb,Rahul Telange,Elizabeth Gardner Grubbs,Angela M Carter

doi:10.18632/oncotarget.26480

Abstract

Medullary thyroid carcinoma (MTC) is a slow growing neuroendocrine (NE) tumor for which few treatment options are available. Its incidence is rising and mortality rates have remained unchanged for decades. Increasing the repertoire of available treatments is thus crucial to manage MTC progression. Scarcity of patient samples and of relevant animal models are two challenges that have limited the development of effective non-surgical treatments. Here we use a clinically accurate mouse model of MTC to assess the effects and mode of action of the tyrosine kinase inhibitor (TKI) Vandetanib, one of only two drugs currently available to treat MTC. Effects on tumor progression, histopathology, and tumorigenic signaling were evaluated. Vandetanib blocked MTC growth through an anti-angiogenic mechanism. Furthermore, Vandetanib had an apparent anti-angiogenic effect in a patient MTC sample. Vandetanib displayed minimal anti-proliferative effects in vivo and in human and mouse MTC tumor-derived cells. Based on these results, we evaluated the second-generation TKI, Nintedanib, alone and in combination with the histone deacetylase (HDAC) inhibitor, Romidepsin, as potential alternative treatments to Vandetanib. Nintedanib showed an anti-angiogenic effect while Romidepsin decreased proliferation. Mechanistically, TKIs attenuated RET-, VEGFR2- and PI3K/AKT/FOXO signaling cascades. Nintedanib alone or in combination with Romidepsin, but not Vandetanib, inhibited mTOR signaling suggesting Nintedanib may have broader anti-cancer applicability. These findings validate the MTC mouse model as a clinically relevant platform for preclinical drug testing and reveal the modes of action and limitations of TKI therapies.

Highlights

Medullary thyroid carcinoma (MTC) is a rare indolent cancer derived from calcitonin secreting C-cells of the thyroid gland, which occurs either as a sporadic or hereditary disease [1]
These findings indicate that tyrosine kinase inhibitor (TKI)-based treatments inhibited the PI3K/AKT pathway, and support the observation that phospho-Thr308 is a better marker of AKT activity than phospho-Ser473 [28]
Vandetanib had no effects on mTOR. Together these findings indicate that Vandetanib and Nintedanib use different mechanisms downstream of PI3K/AKT to stop MTC growth, the two TKIs show several mechanistic similarities

Summary

Introduction

MTC is a rare indolent cancer derived from calcitonin secreting C-cells of the thyroid gland, which occurs either as a sporadic or hereditary disease [1]. Most MTC patients carry activating mutations in the Rearranged-during-transfection (RET) gene, which encodes a receptor tyrosine kinase [2, 3]. Two TKIs, Vandetanib and Cabozantinib, have been approved for the treatment of advanced MTC patients [5,6,7]. Expanding the repertoire of therapies available for the treatment of MTC and other NE cancers is essential. Defining the mode of action of current MTC drugs would advance our understanding of relevant oncogenic signaling pathways and could suggest additional drugs or combinations to more effectively treat these cancers

Methods

Results

Conclusion