Maximizing Effectiveness of Radioiodine Therapy by Inhibiting MAPK Signaling

通过抑制 MAPK 信号传导最大限度地提高放射性碘治疗的有效性

• 批准号: 8738870
• 负责人: JAMES A FAGIN
• 金额: $ 33.02万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-19 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8738870
• 关键词: Adverse effects; Avidity; BRAF gene; Cells; Clinical; Clinical Trials; Combined Modality Therapy; Down-Regulation; ERBB3 gene; Effectiveness; Feedback; Gene Expression; Goals; I131 isotope; Institutional Review Boards; Iodide Peroxidase; Iodides; Iodine; Kinetics; MEKs; Malignant neoplasm of thyroid; Memorial Sloan-Kettering Cancer Center; Mitogen-Activated Protein Kinase Inhibitor; Mitogen-Activated Protein Kinases; Mus; Mutation; Neoplasm Metastasis; Oncogenes; Oncogenic; Operative Surgical Procedures; Papillary thyroid carcinoma; Pathway interactions; Patients; Positron-Emission Tomography; Postoperative Period; Proteins; Radioactive Iodine; Receptor Protein-Tyrosine Kinases; Refractory; Research; Resistance; Role; Signal Pathway; Signal Transduction; Site; Sodium Iodide; Testing; Thyroid Gland; Thyroid Hormones; Tissues; Toxic effect; Treatment Efficacy; Up-Regulation; base; cancer cell; cell type; dosimetry; hormone biosynthesis; improved; inhibitor/antagonist; insight; kinase inhibitor; mouse model; mutant; outcome forecast; research study; response; small molecule; therapy resistant; tumor; uptake

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 nnutation 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 HERS, which confers resistance to therapy. In addition, activation of TGFp 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 TGFp signaling enhance iodide uptake alone or in combination with inhibitors of the RAF-MEK-ERK pathway.4) Evaluate the response to 1311 therapy of murine thyroid cancers pretreated with the combination therapy/s showing the best effects on 1241 dosimetry.

甲状腺细胞中MAPK的致癌性激活导致甲状腺癌所需基因表达的缺失 激素生物合成，包括钠碘转运蛋白（NIS）和甲状腺过氧化物酶（TPO）。肿瘤 具有BRAF突变的PTCs具有较低的NIS表达，这可能解释了为什么BRAF突变的PTCs通常 对RAI疗法有抵抗力。我们开发了由BRAF-V600E驱动的甲状腺癌小鼠模型， 肿瘤也失去了浓缩放射性碘的能力，而这种能力可以通过RAF或MEK治疗来恢复 抑制剂的此外，MEK抑制剂AZD6244重新激活了转移部位的碘摄取， RAI难治性甲状腺癌，允许他们中的许多人用131碘治疗，具有显着的临床 应答尽管MEK抑制剂不能完全阻断MAPK信号转导，但仍观察到这些有益的结果。 甲状腺癌细胞，因为它们缓解了导致受体酪氨酸激酶上调的反馈， 特别是HERS，它赋予对治疗的抗性。此外，TGF β信号传导的激活， 晚期甲状腺癌的共同特征，可能进一步诱导MAPK应答 抑制剂，导致NIS的进一步下调。本项目的目标是确定如何优化 抑制MAPK信号传导以进一步增强放射性碘摄取和对RAI治疗的反应 甲状腺癌这将通过以下具体目标来实现：1）确定MEK的效果 抑制剂对转移性RAI难治性甲状腺癌患者碘-124掺入的动力学， 并测试这是由于增加的基因表达所需的掺入的假设， 无机碘化物转化为蛋白质。2)确定靶向MAPK和HER3的抑制剂组合是否 在BRAF小鼠模型中，信号传导比单一药物更有效地恢复RAI掺入。 诱发甲状腺癌。3)确定TGF β信号传导的药理学抑制剂是否增强碘摄取 单独或与RAF-MEK-ERK通路的抑制剂组合。 用联合疗法预处理的鼠甲状腺癌的治疗显示出对1241的最佳效果 剂量测定法