Non-invasive characterization of tumor response to protein kinase inhibitor therapy by PET imaging

本提案的目的是表征肿瘤对braf和MEK抑制剂治疗的反应以及肿瘤在体外和体内的代谢。该提案的两个目的之一是研究靶向治疗药物与甲状腺癌（一种具有高频率braf突变的肿瘤实体）中GLUT-1(3)表达和F-18-FDG摄取之间的相互作用。与恶性黑色素瘤相反，甲状腺癌通常对braf抑制具有抗性。耐药机制涉及刺激HER3受体的生长因子heregulin的过度表达。我们想要确定在vemurafenib和拉帕替尼治疗（单药和联合治疗）的情况下，肿瘤细胞培养中细胞膜和细胞质中GLUT-1/GLUT-3的表达。下一步，我们希望在几个时间点评估vemurafenib和拉帕替尼（单药和联合治疗）治疗时的GLUT-1(3)表达，然后评估治疗期间糖酵解关键酶的活性，并与GLUT-1(3)表达进行比较。最后一步是将肿瘤细胞培养物植入小鼠体内，评估FDG PET单独和联合抑制剂治疗的体内效果。本提案的第二个目的是研究碘和FDG储存的反比关系，即甲状腺癌中所谓的“翻转现象”。最近的临床研究表明，使用selumetinib治疗可以显著增加转移性甲状腺癌的放射性碘摄取。我们将使用raf抑制剂vemurafenib和MEK抑制剂selumetinib使用细胞系来研究flip - flop现象。低碘和高FDG储存之间是否存在关系，反之亦然？更有趣的是，在BRAF抑制剂治疗期间，细胞是否有一个储存最多碘的时间段？将甲状腺肿瘤细胞系植入小鼠模型，观察体内观察结果

The aim of this proposal is to characterize tumor response to braf and MEK inhibitor therapy and tumor metabolism in vitro and in vivo. One of the two aims of this proposal is to investigate the interaction between targeted therapy drugs and GLUT-1 (3) expression and F-18-FDG uptake in thyroid cancer, a tumor entity that has a high frequency of braf mutations. In contrast to malignant melanoma thyroid cancers are frequently resistant to braf inhibition. The resistance mechanism involves overexpression of the growth factor heregulin which stimulates HER3 receptors. We want to determine the GLUT-1/GLUT-3 expression in the cell membrane and in cytosol in tumor cell culture in case of therapy with vemurafenib and lapatinib (single- and combination therapy). In the next step we want to evaluate the GLUT-1 (3) expression in case of therapy with vemurafenib and lapatinib (single- and combination therapy) for several time points and then to evaluate the activity of the key enzymes of glycolysis during therapy and comparison with GLUT-1 (3) expression. The last step is to implant the tumor cell culture into mice and to evaluate the effects of the single and combination inhibitor therapy with FDG PET in vivo.The second aim of this proposal is to investigate the inverse relationship of iodine- and FDG storage, the so called flip-flop-phenomenon, in thyroid cancer. Recent clinical studies have indicated that treatment with selumetinib can dramatically increase radioiodine uptake of metastatic thyroid cancer. We will use cell lines to investigate the flip flop-phenomenon using a RAF-inhibitor vemurafenib and the MEK inhibitor selumetinib. Is there a relationship between low iodine and high FDG storage and vice versa? And more interestingly, is there a time slot in which the cells store maximum iodine during the therapy with BRAF inhibitors? Implanting the thyroid tumor cell lines into mice models to investigate observed results in vivo