Maximizing effectiveness of radioiodine therapy by inhibition of MAPK signaling

描述(由申请人提供)：甲状腺细胞中MAPK的致癌激活导致甲状腺激素生物合成所需基因的表达缺失，包括钠碘转运体(NIS)和甲状腺过氧化物酶(TPO)。具有BRAF突变的肿瘤有较低的NIS表达，这可能解释了为什么BRAF突变的PTCs经常对RAI治疗耐药。我们建立了由BRAF-V600E驱动的小鼠甲状腺癌模型，这些肿瘤也失去了浓缩放射性碘的能力，而放射性碘可以通过RAF或MEK抑制剂治疗而恢复。此外，MEK抑制剂AZD6244重新激活了RAI难治性甲状腺癌患者转移部位的碘摄取，使许多患者能够接受131-碘治疗，具有显著的临床疗效。这些有益的结果是可以看到的，尽管MEK抑制剂并不能完全阻断甲状腺癌细胞中的MAPK信号，因为它们缓解了导致受体酪氨酸激酶上调的反馈，特别是导致治疗抵抗的HER3。此外，晚期甲状腺癌的共同特征是转化生长因子信号的激活，MAPK抑制剂可能会进一步诱导这一信号通路的激活，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抑制剂对慢性支气管炎患者碘-124掺入动力学的影响 转移性RAI难治性甲状腺癌，并检验这是由于蛋白质中加入无机碘所需的基因表达增加所致。2)确定是否存在 在BRAF诱导的小鼠甲状腺癌模型中，靶向MAPK和HER3信号的联合抑制剂在恢复RAI掺入方面比单一药物更有效。3)确定转化生长因子β信号通路的药理抑制剂是否单独或与RAF-MEK-ERK途径的抑制剂联合使用促进碘摄取。4)评价131I治疗的反应，经联合治疗的小鼠甲状腺癌/S显示最好的124I剂量学效果。

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.