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，该研究将评估 MEK 1/2 抑制剂曲美替尼（葛兰素史克，GSK1120212）恢复放射性碘 (RAI) 掺入的能力以及对 RAS 突变体 (MUT) 或 BRAF/RAS 野生型 (WT)、RAI 难治性患者的疗效(RAIR) 甲状腺癌。该试验将作为一项多中心研究进行，MSKCC 为牵头中心，NIH 为合作中心。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 耐药，预示着预后不良。甲状腺乳头状癌 (PTC) 与编码丝裂原激活蛋白激酶 (MAPK) 信号通路（即 RET、NTRK、RAS 和 BRAF）效应子的癌基因的互斥突变相关。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而导致 RAI 难治性。在甲状腺癌小鼠模型中，我们发现对 MAPK 通路的药物抑制可以恢复这些基因的表达以及肿瘤捕获 RAI 的能力。基于这些观察结果，我们进行了一项试点临床试验，证明 MEK 抑制剂 selumetinib（阿斯利康）可以恢复 RAIR 患者子集的 RAI 疗效。 124I PET/CT 扫描用于量化司美替尼诱导的个体甲状腺肿瘤内碘掺入的变化，并预测治疗 131I 的临床疗效，这是一种称为“病变剂量测定”的创新分析技术。这种方法对于 RAS MUT 癌症特别有效； BRAF/RAS WT 肿瘤观察到更多异质性结果。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 患者的 RAI 疗效的假设。核心假设是，需要最大程度的 MEK 抑制才能最佳地恢复 RAS MUT 和 BRAF/RAS WT RAIR 甲状腺癌患者的 RAI 疗效，我们建议使用更有效的 MEK 抑制剂曲美替尼 (trametinib) 进行一项临床试验，以恢复这些患者的 RAI 掺入（通过 124I PET 病灶剂量测定法测量）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联（AIM #2）。使用靶向治疗来恢复 RAI 疗效、进行 124I PET 病灶剂量测定来指导 RAI 的临床使用以及开发治疗 RAS MUT 疾病的新型靶向方法代表了 RAIR 甲状腺癌治疗范式转变的进展，这也可能对其他癌症产生影响，在这些癌症中，可以探索“再分化”概念作为新疗法。

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.