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

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

Research output: Contribution to journalArticle

3 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)37662-37675
Number of pages14
JournalOncotarget
Volume9
Issue number102
StatePublished - Dec 1 2018

Keywords

  • Animal model
  • Medullary thyroid carcinoma
  • Targeted therapy
  • Tyrosine kinase inhibitors
  • Vandetanib

ASJC Scopus subject areas

  • Oncology

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    Pozo, K., Zahler, S., Ishimatsu, K., Carter, A. M., Telange, R., Tan, C., Wang, S., Pfragner, R., Fujimoto, J., Grubbs, E. G., Takahashi, M., Oltmann, S. C., & Bibb, J. A. (2018). Preclinical characterization of tyrosine kinase inhibitor-based targeted therapies for neuroendocrine thyroid cancer. Oncotarget, 9(102), 37662-37675.