EXPLOITATION OF RET INHIBITORS FOR TREATMENT OF THYROID CANCER

该项目将利用一个独特的机会开发甲状腺癌的靶向治疗。 我们和其他人已经发现ras/raf/MEK信号转导通路被特定的遗传因子激活， 几乎所有的乳头状甲状腺癌病例都发生了这种情况，我们最近发现甲状腺癌细胞 细胞系对MEK抑制非常敏感。此外，MEK抑制导致一组基因上调 甲状腺特异性基因对碘吸收的必要性。在这个项目中，我们将继续研究这些发现， 并将MEK抑制剂单独或联合用于甲状腺疾病治疗的最佳策略转化为 癌 甲状腺癌细胞系对AZD 6244（一种新型MEK抑制剂）的敏感性将在两种细胞中进行评估， 培养物和异种移植物中，并与BRAF和其他突变状态相关。PI 3 K的潜在作用 将评估作为MEK抑制的逃逸途径的一种途径。潜在的分子标记 将开发药物的功效， 为了开发联合治疗方法，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，我们将专注于PI 3 K信号 转导途径，因为它已被证明在大多数甲状腺癌病例中被激活;另外 还将评估有希望的途径。一种潜在的突变，赋予AZD 6244耐药性， 甲状腺癌细胞系，将进行探索。这种突变可能表明对AZD 6244的固有抗性，或 可能是AZD 6244治疗期间产生耐药性的潜在机制。 单独和组合的MEK抑制诱导生物学相关的细胞再活化的能力被证明是有效的。 将在细胞培养物和异种移植模型中评估碘摄取。这些研究将提供 关于这种新型MEK抑制剂对甲状腺肿瘤分化影响的重要分子信息 细胞，并将成为这些药物对甲状腺癌患者的未来临床试验的基础。 相关性：美国每年约有26，000例甲状腺癌新发病例， 在过去的三十年里，增长了一倍。在这些病例中，约有10%的病例复发， 放射性碘和其它治疗难以治愈，死亡率很高。我们的研究是针对 甲状腺癌的治疗，将解决这一未满足的医疗需求。

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.