Maximizing effectiveness of radioiodine therapy by inhibition of MAPK signaling

描述（由申请方提供）：甲状腺细胞中MAPK的致癌性激活导致甲状腺激素生物合成所需基因表达缺失，包括碘化钠转运蛋白（NIS）和甲状腺过氧化物酶（TPO）。具有BRAF突变的肿瘤具有较低的NIS表达，这可能解释了为什么BRAF突变的PTC通常对RAI治疗具有抗性。我们开发了由BRAF-V600 E驱动的甲状腺癌小鼠模型，这些肿瘤也失去了浓缩放射性碘的能力，通过RAF或MEK抑制剂治疗可以恢复。此外，MEK抑制剂AZD 6244重新激活了RAI难治性甲状腺癌患者转移部位的碘摄取，使其中许多人能够用131-碘治疗，具有显著的临床反应。尽管MEK抑制剂不能完全阻断甲状腺癌细胞中的MAPK信号传导，但观察到这些有益的结果，因为它们缓解了导致受体酪氨酸激酶（特别是HER 3）上调的反馈，这赋予了对治疗的抗性。此外，TGF β信号传导的激活，这是晚期甲状腺癌的一个共同特征，可能会进一步诱导MAPK抑制剂的反应，导致NIS的进一步下调。该项目的目标是确定如何优化MAPK信号的抑制，以进一步增强甲状腺癌的放射性碘摄取和对RAI治疗的反应。这将通过以下具体目标来完成：1）确定MEK抑制剂对患有以下疾病的患者中碘-124掺入动力学的影响： 转移性RAI难治性甲状腺癌，并测试这是由于无机碘掺入蛋白质所需的基因表达增加的假设。2)确定是否 在BRAF诱导的甲状腺癌的小鼠模型中，靶向MAPK和HER 3信号传导的抑制剂的组合在恢复RAI掺入方面比单一药剂更有效。3)确定TGF β信号传导的药理学抑制剂是否单独或与RAF-MEK-ERK通路的抑制剂组合增强碘摄取。4）评价用组合疗法预处理的鼠甲状腺癌对131 I疗法的响应，所述组合疗法显示对124 I剂量测定的最佳效果。

DESCRIPTION (provided by applicant): Oncogenic activation of MAPK in thyroid cells leads to loss of expression of genes required for thyroid hormone biosynthesis, including the sodium iodide transporter (NIS) and thyroid peroxidase (TPO). Tumors with BRAF mutation have lower expression of NIS, which likely explains why BRAF mutant PTCs are often resistant to RAI therapy. We developed mouse models of thyroid cancer driven by BRAF-V600E, and these tumors also lose the ability to concentrate radioiodine, which is restored by treatment with RAF or MEK inhibitors. Moreover, the MEK inhibitor AZD6244 reactivated iodide uptake at metastatic sites in patients with RAI- refractory thyroid cancer, allowing many of them to be treated with 131-iodine, with remarkable clinical responses. These beneficial results were seen although MEK inhibitors do not fully block MAPK signaling in thyroid cancer cells, because they relieve a feedback leading to upregulation of receptor tyrosine kinases, in particular HER3, which confers resistance to therapy. In addition, activation of TGF¿ signaling, which is a common feature of advanced forms of thyroid cancer, may be further induced in response to MAPK inhibitors, leading to further downregulation of NIS. The goals of this project are to determine how to optimize inhibition of MAPK signaling to further enhance radioactive iodine uptake and response to RAI therapy in thyroid cancer. This will be done through the following specific aims: 1) Determine the effect of MEK inhibitors on the kinetics of iodine-124 incorporation in patients with metastatic RAI refractory thyroid cancer, and test the hypothesis that this is due to increased expression of genes required for incorporation of inorganic iodide into proteins. 2) Determine if a combination of inhibitors that target MAPK and HER3 signaling is more effective in restoring RAI incorporation than the single agents in mouse models of BRAF-induced thyroid cancers. 3) Determine if pharmacological inhibitors of TGF¿ signaling enhance iodide uptake alone or in combination with inhibitors of the RAF-MEK-ERK pathway.4) Evaluate the response to 131I therapy of murine thyroid cancers pretreated with the combination therapy/s showing the best effects on 124I dosimetry.