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

靶向 MEK 恢复放射性碘治疗 RAI 难治性甲状腺癌的疗效

• 批准号: 8818439
• 负责人: Alan L. Ho
• 金额: $ 52.66万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8818439
• 关键词: Avidity; Award; BRAF gene; Cancer Patient; Cancer Therapy Evaluation Program; Cells; Cessation of life; Clinical; Clinical Trials; Conduct Clinical Trials; Data; Dependence; Disease; Dose; Effectiveness; Future; Gene Expression; Gene Expression Profile; Genome; Genomics; Genotype; Goals; Individual; Iodine; Lead; Link; MEK inhibition; MEKs; Malignant Neoplasms; Malignant neoplasm of thyroid; Measures; Memorial Sloan-Kettering Cancer Center; Mitogen-Activated Protein Kinases; Multicenter Studies; Mutation; Oncogenes; Oncogenic; Other Genetics; Outcome; PET/CT scan; Papillary thyroid carcinoma; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pilot Projects; Population; Positron-Emission Tomography; Protocols documentation; Radiation; Radioactive Iodine; Refractory; Resistance; Scanning; Signal Pathway; Signal Transduction; Site; Systemic Therapy; Techniques; Therapeutic; Thyroid Gland; Tissues; United States National Institutes of Health; base; clinical efficacy; clinically relevant; dosimetry; inhibitor/antagonist; innovation; insight; interest; kinase inhibitor; mouse model; mutant; novel; novel strategies; outcome forecast; phase 2 study; public health relevance; research study; response; restoration; small molecule; targeted treatment; therapy development; thyroid neoplasm; trial design; tumor; uptake

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.

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Trametinib（GlaxoSmithKline，GSK1120212）的能力，以恢复Radioodine（RAI）（RAI）（RAI）（RAI）或BRBRAS MUTAFT（MUTAS）（WT）（WT）（WT Rai-Refractory（Rair）甲状腺癌。该试验将以MSKCC作为铅中心和NIH协作站点作为多中心研究。转移性疾病是甲状腺癌相关死亡的最常见原因，RAI（OR 131i）仍然是这些患者治疗的主要治疗方法。不幸的是，许多甲状腺癌患者的肿瘤不再捕获碘，因此对RAI难治性，预后不佳。乳头状甲状腺癌（PTC）与有丝分裂原活化蛋白激酶（MAPK）信号通路的癌基因的互斥突变有关（即RET，NTRK，RAS和BRAF）。甲状腺细胞中MAPK信号传导的致癌激活通过抑制碘摄取和保留所需的基因的表达来促进RAI耐磨性。在甲状腺癌的小鼠模型中，我们发现对MAPK途径的药理抑制恢复了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，我们进行了一项试验临床试验，该试验表明MEK抑制剂selumetinib（阿斯利康）可以在RAIR患者的一部分中恢复RAI功效。 124i PET/CT扫描用于量化甲状腺替尼在个别甲状腺肿瘤中碘掺入的变化，并预测治疗131i的临床疗效，这是一种创新的分析技术，称为“剂量剂量法”。这种方法对RAS群癌特别有效。对于BRAF/RAS WT肿瘤观察到了更异质的结果。现在需要的是概念验证，以基因型为中心的临床试验，以确定这是否是治疗RAS MUT疾病的临床有效靶向方法，并探讨了以下假设：更有效的MEK抑制可以优化BRAF/RAS WT患者RAI功效。通过以下中心假设：需要最佳的MEK抑制作用才能最佳地恢复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Trametib进行临床试验进行临床试验，以恢复RAI掺入（通过124i Pet pet pet pet to pet to pet simiation dosiality dosimet dosimetry and Efficacy and Efficacy and aim）和这些患者。我们还将进行相关组织研究，以确定基因组景观和曲米尼诱导的基因表达变化与药物对肿瘤内RAI作用的临床影响相关（AIM＃2）。使用有针对性的治疗来恢复RAI功效，进行124i PET剂量剂量测定法以指导RAI的临床使用，并开发了一种新颖的靶向方法来治疗Ras Mut疾病，代表了范式转化的范例，可以治疗Rair甲状腺癌的治疗，这也可以对其他癌症造成其他含义，而这些癌症也对此构成了其他“重新分解”的概念。