Research Papers:
Preclinical characterization of tyrosine kinase inhibitor-based targeted therapies for neuroendocrine thyroid cancer
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Abstract
Karine Pozo1,2, Stefan Zahler3, Keisuke Ishimatsu4, Angela M. Carter5, Rahul Telange5, Chunfeng Tan6, Shuaijun Wang3, Roswitha Pfragner7, Junya Fujimoto8, Elizabeth Gardner Grubbs9, Masaya Takahashi4, Sarah C. Oltmann2 and James A. Bibb5,10
1Department of Neuroscience, The University of Texas Southwestern Medical Center, Dallas, TX, USA
2Department of Surgery, The University of Texas Southwestern Medical Center, Dallas, TX, USA
3Center for Drug Research, Ludwig-Maximilians-Universität, Munich, Germany
4Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas, TX, USA
5Department of Surgery, The University of Alabama, Birmingham, AL, USA
6Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX, USA
7Institute of Pathophysiology and Immunology, Medical University of Graz, Graz, Austria
8Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
9Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
10Comprehensive Cancer Center, The University of Alabama at Birmingham Medical Center, Birmingham, AL, USA
Correspondence to:
James A. Bibb, email: [email protected]
Keywords: medullary thyroid carcinoma; tyrosine kinase inhibitors; vandetanib; targeted therapy; animal model
Received: September 17, 2018 Accepted: December 05, 2018 Published: December 28, 2018
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.
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