Pozo Karine, Zahler Stefan, Ishimatsu Keisuke, Carter Angela M, Telange Rahul, Tan Chunfeng, Wang Shuaijun, Pfragner Roswitha, Fujimoto Junya, Grubbs Elizabeth Gardner, Takahashi Masaya, Oltmann Sarah C, Bibb James A
Department of Neuroscience, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
Department of Surgery, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
Oncotarget. 2018 Dec 28;9(102):37662-37675. doi: 10.18632/oncotarget.26480.
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 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.
甲状腺髓样癌（MTC）是一种生长缓慢的神经内分泌（NE）肿瘤，目前针对该肿瘤的治疗选择有限。其发病率正在上升，而死亡率几十年来一直保持不变。因此，增加可用治疗方法的种类对于控制MTC进展至关重要。患者样本和相关动物模型的稀缺是限制有效非手术治疗发展的两个挑战。在此，我们使用一种临床准确的MTC小鼠模型来评估酪氨酸激酶抑制剂（TKI）凡德他尼的作用效果和作用模式，凡德他尼是目前仅有的两种可用于治疗MTC的药物之一。评估了其对肿瘤进展、组织病理学和肿瘤发生信号传导的影响。凡德他尼通过抗血管生成机制阻断MTC生长。此外，凡德他尼在一份患者MTC样本中具有明显的抗血管生成作用。凡德他尼在人源和鼠源MTC肿瘤衍生细胞中显示出最小的抗增殖作用。基于这些结果，我们评估了第二代TKI尼达尼布单独使用以及与组蛋白去乙酰化酶（HDAC）抑制剂罗米地辛联合使用，作为凡德他尼的潜在替代治疗方法。尼达尼布显示出抗血管生成作用，而罗米地辛可降低增殖。从机制上讲，TKIs减弱了RET、VEGFR2和PI3K/AKT/FOXO信号级联反应。单独使用尼达尼布或与罗米地辛联合使用，但凡德他尼不行，可抑制mTOR信号传导，这表明尼达尼布可能具有更广泛的抗癌适用性。这些发现验证了MTC小鼠模型作为临床相关的临床前药物测试平台的有效性，并揭示了TKI疗法的作用模式和局限性。
