EXPLOITATION OF RET INHIBITORS FOR TREATMENT OF THYROID CANCER

该项目将利用一个独特的机会来开发针对甲状腺癌的靶向治疗。 我们和其他人发现ras/raf/mek信号转导通路是由特定的基因激活的。 事件发生在几乎所有的甲状腺乳头状癌病例中，我们最近发现，甲状腺癌细胞 品系对MEK抑制非常敏感。此外，抑制MEK会导致一组基因的上调 摄取碘所必需的甲状腺特异基因。在这个项目中，我们将继续研究这些发现以开发 并将MEK抑制剂单独或联合使用治疗甲状腺的最佳策略转化为 癌症。 甲状腺癌细胞系对新型MEK抑制剂AZD6244的敏感性将在两个细胞内进行评估 在培养和异种移植中，与BRAF和其他突变状态相关。PI3K的潜在作用 作为逃避MEK抑制的逃逸途径，将对此进行评估。潜在的分子标记 这种药物的疗效将被开发出来， 开发联合治疗方法，在甲状腺中激活的信号转导通路 癌细胞将被评估为潜在的治疗靶点。首先，我们将集中讨论PI3K信号 转导通路，因为它在大多数甲状腺癌病例中被激活； 有希望的途径也将得到评估。一种潜在的突变，赋予对AZD6244的抗性 甲状腺癌细胞株，将进行探索。这种突变可能表明对AZD6244具有内在抗药性，或者 这可能是AZD6244治疗过程中产生耐药性的潜在机制。 MEK抑制，单独或联合，诱导生物相关的再激活的能力 碘的摄取将在细胞培养和异种移植模型中进行评估。这些研究应该提供 新型MEK抑制剂对甲状腺肿瘤分化影响的重要分子信息 细胞，并将成为这些药物未来在甲状腺癌患者上进行临床试验的基础。 相关性：美国每年约有26,000例新的甲状腺癌病例，其中3例为 在过去的三十年里翻了一番。在这些病例中，约有10%是复发性疾病， 对放射性碘和其他疗法无效，有相当大的死亡率。我们的研究要有针对性地发展 治疗甲状腺癌，将解决这一未得到满足的医疗需求。

This project will take advantage of a unique opportunity to develop targeted therapy for thyroid cancer. We and others have found that the ras/raf/MEK signal transduction pathway is activated by specific genetic events in almost all cases of papillary thyroid cancer, and we have recently shown that thyroid cancer cell lines are remarkably sensitive to MEK inhibition. In addition, MEK inhibition leads to upregulation of a group of thyroid-specific genes necessary for iodine uptake. In this project, we will pursue these findings to develop and translate optimal strategies for use of MEK inhibitors, alone and in combination, for therapy of thyroid cancer. Sensitivity of thyroid cancer cell lines to AZD6244, a novel MEK inhibitor, will be evaluated both in cell culture and in xenografts, and correlated with BRAF and other mutation status. The potential role of the PI3K pathway as an escape pathway from MEK inhibition will be evaluated. Potential molecular markers for efficacy of the drug will be developed, To develop combination therapy approaches, signal transduction pathways that are activated in thyroid cancer cells will be evaluated as potential therapeutic targets. Initially, we will concentrate on the PI3K signal transduction pathway, since it has been shown to be activated in most cases of thyroid cancer; additional promising pathways will also be evaluated. A potential mutation, conferring resistance to AZD6244 in a thyroid cancer cell line, will be explored. Such a mutation could indicate inherent resistance to AZD6244, or could be a potential mechanism for development of resistance during AZD6244 treatment. The ability of MEK inhibition, alone and in combination, to induce biologically relevant reactivation of iodine uptake will be assessed in cell culture and in xenograft models. These studies should provide important molecular information on the effects of this novel MEK inhibitor on differentiation in thyroid tumor cells, and will form the basis for future clinical trials of these drugs on thyroid cancer patients. Relevance: There are approximately 26,000 new cases of thyroid cancer per year in the United States, a 3- fold increase in the past three decades. In approximately 10% of these cases there is recurrent disease that is refractory to radioiodine and other therapy, with substantial mortality. Our studies to develop targeted therapy for thyroid cancer, will address this unmet medical need.