Selective Modulation of Thyroidal Radioiodine

甲状腺放射性碘的选择性调节

• 批准号: 8839722
• 负责人: Sissy M Jhiang
• 金额: $ 33.83万
• 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 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8839722
• 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; Radioactive Iodine; 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; microSPECT; mouse model; neoplastic cell; novel; overexpression; pre-clinical; prospective; radioiodine therapy; single photon emission computed tomography; small molecule; symporter; targeted treatment; 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）治疗难治性甲状腺癌患者需要新的治疗方法， 肿瘤通常对外部放射和常规化学疗法具有抗性。到目前为止，没有小说 尽管无进展生存率有所提高，但治疗仍显示出这些患者的总生存率有所提高。 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， 临床试验中的分子抑制剂靶向信号节点，我们和其他人已经证明， 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、Akt、PI 3 K或Hsp 90也将有效增加/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：将 增加甲状腺FiAl积累并鉴定靶向这些的各种抑制剂的机制效应物 信令节点。我们建议：（a）在临床试验中验证选定的抑制剂对增加 （B）确定抑制剂对甲状腺RAI的功效是否 积累在具有不同遗传改变倾向的细胞之间变化;（c）确定机制 每种抑制剂增加RAI积累的基础效应物;和（d）研究可能的 这些信号节点在调节甲状腺RAI中的会聚和动态相互作用 积累目的2：研究甲状腺RAI摄取的增加程度和决定因素 在甲状腺中的不同肿瘤阶段治疗所选抑制剂后每个解剖单位的保留 癌症小鼠模型倾向于具有不同的遗传改变。甲状腺RAI蓄积是 RAI吸收和保留的结合，这两个不同的过程是由 不同的分子我们建议：（a）量化甲状腺RAI摄取和保留每个解剖单位在三个 不同肿瘤阶段的甲状腺癌小鼠模型;（B）鉴定RAI摄取的关键决定因素， 在具有明显遗传改变倾向的甲状腺肿瘤中的保留;（c）确定增加的程度 在上述小鼠模型的甲状腺肿瘤中， （d）确定甲状腺癌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。