Targeting MEK to Restore Radioiodine Efficacy for RAI-Refractory Thyroid Cancer

描述（由申请人提供）：这是一项新的3年R01申请，涉及NCI/CTEP授予的II期研究，将评估MEK 1/2抑制剂trametinib（葛兰素史克公司，GSK1120212）恢复放射性碘（RAI）结合的能力和对RAS突变（MUT）或BRAF/RAS野生型（WT）， RAI难治性（RAIR）甲状腺癌患者的疗效。该试验将作为一项多中心研究进行，MSKCC为牵头中心，NIH为合作站点。转移性疾病是甲状腺癌相关死亡的最常见原因，RAI（或131I）仍然是这些患者的主要治疗方法。不幸的是，许多甲状腺癌患者的肿瘤不再捕获碘，因此对RAI难治，预示着预后不良。甲状腺乳头状癌（PTC）与编码丝裂原活化蛋白激酶（MAPK）信号通路效应子（即RET、NTRK、RAS和BRAF）的癌基因互斥突变有关。甲状腺细胞中MAPK信号的致癌激活通过抑制碘摄取和保留所需基因的表达，有助于RAI的难治性。在甲状腺癌小鼠模型中，我们发现药物抑制MAPK通路恢复了这些基因的表达和肿瘤捕获RAI的能力。基于这些观察，我们进行了一项试点临床试验，该试验表明MEK抑制剂selumetinib （AstraZeneca）可以恢复一部分RAIR患者的RAI疗效。PET/CT扫描用于量化selumetinib诱导的个体甲状腺肿瘤内碘掺入的变化，并预测治疗性碘的临床疗效，这是一种称为“病灶剂量学”的创新分析技术。这种方法对RAS MUT癌症特别有效；在BRAF/RAS WT肿瘤中观察到更多异质性的结果。现在需要的是一项概念验证，以基因型为重点的临床试验，以确定这是否是治疗RAS MUT疾病的临床有效的靶向方法，并探索更有效的MEK抑制可以优化BRAF/RAS WT患者RAI疗效的假设。我们的中心假设是，对于RAS MUT和BRAF/RAS WT RAIR甲状腺癌患者，需要最大程度的MEK抑制才能最佳地恢复RAI疗效，我们建议在这些患者中使用更有效的MEK抑制剂曲美替尼进行临床试验，以恢复RAI的结合（通过124I PET病变剂量测定）和疗效（AIM #1）。我们还将进行相关组织研究，以确定基因组景观和曲美替尼诱导的基因表达变化如何与药物对肿瘤内RAI作用的临床影响相关（AIM #2）。使用靶向治疗来恢复RAI的疗效，进行124I PET病变剂量测定来指导RAI的临床应用，以及开发一种新的靶向治疗RAS MUT疾病的方法，这些都代表了治疗RAIR甲状腺癌的范式转变进展，也可能对其他癌症有启示，其中“再分化”概念可能被探索为新疗法。

DESCRIPTION (provided by applicant): This is a new 3-year R01 application involving a NCI/CTEP awarded phase II study that will evaluate the ability of the MEK 1/2 inhibitor trametinib (GlaxoSmithKline, GSK1120212) to restore radioiodine (RAI) incorporation and efficacy for patients with RAS mutant (MUT) or BRAF/RAS wild-type (WT), RAI-refractory (RAIR) thyroid cancers. This trial will be conducted as a multicenter study with MSKCC as the lead center and the NIH a collaborating site. Metastatic disease represents the most frequent cause of thyroid cancer-related death, and RAI (or 131I) remains a mainstay of therapy for these patients. Unfortunately, many thyroid cancer patients have tumors that no longer trap iodine, and are hence refractory to RAI, heralding a poor prognosis. Papillary thyroid cancers (PTC) are associated with mutually exclusive mutations of oncogenes encoding effectors of the mitogen activated protein kinase (MAPK) signaling pathway (i.e. RET, NTRK, RAS and BRAF). Oncogenic activation of MAPK signaling in thyroid cells contributes to RAI refractoriness by suppressing the expression of genes required for iodine uptake and retention. In mouse models of thyroid cancer, we discovered that pharmacologic inhibition of the MAPK pathway restored the expression of these genes and the ability of tumors to trap RAI. Based on these observations, we conducted a pilot clinical trial which demonstrated that the MEK inhibitor selumetinib (AstraZeneca) can restore RAI efficacy in a subset of RAIR patients. 124I PET/CT scans were used to quantify selumetinib-induced changes in iodine incorporation within individual thyroid tumors and predict the clinical efficacy of therapeutic 131I, an innovative analytic technique termed "lesional dosimetry". This approach was particularly effective for RAS MUT cancers; more heterogeneous results were observed for BRAF/RAS WT tumors. What is now required is a proof-of-concept, genotype-focused clinical trial to determine if this is a clinically effective targeted approach for treating RAS MUT disease, and explore the hypothesis that more potent MEK inhibition can optimize RAI efficacy for BRAF/RAS WT patients. With the central hypothesis that maximal MEK inhibition is required to optimally restore RAI efficacy for RAS MUT and BRAF/RAS WT RAIR thyroid cancer patients, we propose to conduct a clinical trial using the more potent MEK inhibitor trametinib to restore RAI incorporation (measured by 124I PET lesional dosimetry) and efficacy in these patients (AIM #1). We will also perform correlative tissue studies to determine how the genomic landscape and trametinib-induced changes in gene expression correlate to the clinical impact of the drug upon RAI action within tumors (AIM #2). Using a targeted therapy to restore RAI efficacy, conducting 124I PET lesional dosimetry to guide clinical use of RAI, and developing a novel targeted approach for treating RAS MUT disease represent paradigm-shifting advances for the treatment of RAIR thyroid cancers that could also hold implications for other cancers in which "re-differentiation" concepts may be explored as novel therapies.