Selective Modulation of Thyroidal Radioiodine

放射性碘(RAI)治疗无效的甲状腺癌患者需要新的治疗方法，因为他们的 肿瘤一般对外照射和常规化疗有抵抗力。到目前为止，还没有一部小说 尽管改善了无进展的情况，治疗仍显示这些患者的总存活率有所提高。 新出现的靶向治疗方案治疗的一些患者的存活率。我们注意到有几个小的 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，我们假设小分子抑制剂在临床试验中 靶向MEK、B f^F、Akt、PI3K或Hsp90也将有效地增加/恢复甲状腺RAI 积累。为了检验这一假说，本文提出了两个具体目标。目标1：验证信令节点 增加甲状腺FIAL蓄积并识别针对这些的不同抑制剂的机制效应 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)确定抑制剂是否对甲状腺RAI有效 在具有不同遗传改变倾向的细胞中积累不同；(C)确定机制 每种抑制剂增加RAI累积的影响因素；以及(D)调查可能的 甲状腺RAI调控中信号节点间的收敛和动态相互作用 积累。目的2：研究甲状腺RAI摄取增加的程度和潜在的决定因素 以及在甲状腺不同肿瘤阶段治疗所选抑制剂时的单位解剖单位保留率 癌症小鼠模型易发生明显的基因改变。甲状腺RAI积聚是 由RAI摄取和保留的组合贡献，这两个不同的过程由 不同的分子。我们建议：(A)在三个解剖单元中量化甲状腺RAI的摄取和滞留 不同肿瘤阶段的甲状腺癌小鼠模型；(B)确定RAI摄取和 易发生明显遗传改变的甲状腺肿瘤的滞留；(C)确定增加的程度 在上述小鼠甲状腺肿瘤模型中选择性抑制剂对RAI摄取和滞留的影响 不同的肿瘤分期，(D)确定导致甲状腺功能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中，每种抑制物在不同肿瘤阶段的RAI摄取和滞留。

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.