Selective Modulation of Thyroidal Radioiodine

甲状腺放射性碘的选择性调节

• 批准号: 8697755
• 负责人: Sissy M Jhiang
• 金额: $ 32.73万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8697755
• 关键词: Anatomy; BRAF gene; Biological Markers; Cancer Patient; Cells; Clinical Trials; Diagnostic Neoplasm Staging; Epithelial; External Beam Radiation Therapy; Genetic; Iodides; Iodine; Life; MEKs; Malignant Neoplasms; Malignant neoplasm of thyroid; Measurement; Mediating; Messenger RNA; MicroRNAs; Molecular; Molecular Profiling; Monitor; Mus; Mutation; PTEN gene; Pathway interactions; Patients; Process; Progression-Free Survivals; Rattus; Refractory; Regimen; Resistance; Role; Signal Pathway; Signal Transduction; Silicon Dioxide; Small Interfering RNA; Solid Neoplasm; Testing; Thyroid Gland; Tumor stage; Ultrasonography; chemotherapeutic agent; chemotherapy; improved; inhibitor/antagonist; mouse model; neoplastic cell; novel; overexpression; pre-clinical; prospective; single photon emission computed tomography; small molecule; symporter; thyroid neoplasm; tumor; tumor progression; uptake

Patients with thyroid cancer refractory to radioiodine (RAI) treatment are in need for novel treatment as their tumors are generally resistant to external radiation and conventional chemotherapy. To this date, no novel treatment has yet shown improved overall survival for these patients, despite improved progression-free survival in some patients treated with emerging targeted therapy regimen. We noted that several small molecular inhibitors in clinical trials are targeting signaling nodes we and others have shown to modulate thyroidal iodine accumulation. We, thus, hypothesize that small molecule Inhibitors in clinical trials targeting MEK, B f ^ F , Akt, PI3K or Hsp90, will also be effective in increasing/restoring thyroidal RAI accumulation. Two specific aims are proposed to test this hypothesis. Aim 1: Validate signaling nodes that increase thyroidal FiAl accumulation and identify mechanistic effectors of various inhibitors targeting these signaling nodes. We propose to: (a) Validate the effects of selected inhibitors in clinical trials on increasing RAI accumulation in cultured thyroid cells; (b) Determine whether inhibitor's efficacy on thyroidal RAI accumulation vary among cells predisposed with distinct genetic alterations; (c) Identify mechanistic effectors that underlie the increase of RAI accumulation by each inhibitor; and (d) Investigate possible convergence and dynamic interactions among these signaling nodes in modulating thyroidal RAI accumulation. Aim 2: Investigate the extent of increase and underiying determinants in thyroidal RAI uptake and retention per anatomic unit upon treatment of selected inhibitors at various tumor stages in thyroid cancer mouse models predisposed with distinct genetic alterations. Thyroidal RAI accumulation is contributed by the combination of RAI uptake and retention, two distinct processes that are mediated by distinct molecules. We propose to: (a) Quantify thyroidal RAI uptake and retention per anatomic unit in three thyroid cancer mouse models at various tumor stages; (b) Identify critical determinants of RAI uptake and retention in thyroid tumors predisposed with distinct genetic alterations; (c) Determine the extent of increase in RAI uptake and retention by selected inhibitors in thyroid tumors of aforementioned mouse models at various tumor stages, (d) Identify biomarkers and critical determinants that underlie the increase of thyroidal RAI uptake and retention by each inhibitor at various tumor stages of selected thyroid cancer mouse models.

放射性碘 (RAI) 治疗难治的甲状腺癌患者需要新的治疗方法，因为他们的 肿瘤通常对外部放射和常规化疗具有抵抗力。到现在还没有小说 尽管无进展情况有所改善，但治疗尚未显示这些患者的总生存期有所改善 一些接受新兴靶向治疗方案治疗的患者的生存率。我们注意到有几个小 临床试验中的分子抑制剂针对的是我们和其他人已经证明可以调节的信号节点 甲状腺碘蓄积。因此，我们假设临床试验中的小分子抑制剂 靶向 MEK、B f ^ F、Akt、PI3K 或 Hsp90，也可有效增加/恢复甲状腺 RAI 积累。提出了两个具体目标来检验这一假设。目标 1：验证信令节点 增加甲状腺 FiAl 积累并确定针对这些的各种抑制剂的机械效应器 信令节点。我们建议： (a) 在临床试验中验证所选抑制剂对增加 培养的甲状腺细胞中 RAI 积累； (b) 确定抑制剂对甲状腺 RAI 是否有效 具有不同遗传改变倾向的细胞之间的积累有所不同； (c) 确定机制 每种抑制剂增加 RAI 积累的效应子； (d) 调查可能的情况 这些信号节点在调节甲状腺 RAI 中的收敛和动态相互作用 积累。目标 2：研究甲状腺 RAI 摄取的增加程度和潜在决定因素 以及在甲状腺不同肿瘤阶段选择抑制剂治疗后每个解剖单位的保留率 癌症小鼠模型容易发生明显的基因改变。甲状腺 RAI 累积量为 是由 RAI 吸收和保留的结合所促成的，这两个不同的过程由以下因素介导： 不同的分子。我们建议： (a) 将每个解剖单位的甲状腺 RAI 摄取和保留量化为三个 不同肿瘤阶段的甲状腺癌小鼠模型； (b) 确定 RAI 吸收的关键决定因素， 保留在易于发生明显遗传改变的甲状腺肿瘤中； (c) 确定增加的程度 在上述小鼠模型的甲状腺肿瘤中，所选抑制剂对 RAI 的摄取和保留 各个肿瘤阶段，(d) 确定甲状腺激素增加的生物标志物和关键决定因素 在选定的甲状腺癌小鼠模型的不同肿瘤阶段，每种抑制剂对 RAI 的摄取和保留。