124I-NaI PET: Building block for precision medicine in metastatic thyroid cancer

124I-NaI PET：转移性甲状腺癌精准医疗的基石

• 批准号: 9976468
• 负责人: JOHN L HUMM
• 金额: $ 72.34万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-05 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9976468
• 关键词: Ablation; Alternative Therapies; Avidity; BRAF gene; Biological; Cancer Patient; Clinic; Clinical; Clinical Trials; Data; Development; Diagnostic; Discipline of Nuclear Medicine; Disease; Disease Management; Distant Metastasis; Dose; Dysmyelopoietic Syndromes; Dysplasia; ERBB3 gene; Endocrinologist; Evaluation; Gamma Rays; Gene Expression; Genes; Genetic Transcription; Genomics; Genotype; Goals; Heterogeneity; Hospitals; I131 isotope; Image; Individual; Institution; Investigation; Iodides; Iodine; Lacrimal Duct Obstruction; Lesion; Life; Lung; MAP Kinase Gene; MAP3K1 gene; MEKs; Malignant Neoplasms; Malignant neoplasm of thyroid; Marrow; Measurement; Measures; Medical Oncologist; Medicine; Metabolism; Methodology; Methods; Molecular; Monoclonal Antibodies; Morbidity - disease rate; Motion; Neoplasm Metastasis; Normal tissue morphology; Output; Pathway interactions; Patient Care; Patient Selection; Patients; Persons; Pharmaceutical Preparations; Physicians; Physics; Positron-Emission Tomography; Protein-Serine-Threonine Kinases; Protocols documentation; Radiation; Radiation Oncologist; Radiation Tolerance; Radioactive Iodine; Recommendation; Refractory; Refractory Disease; Research; Respiration; Risk; Role; Salivary Glands; Savings; Stable Disease; Structure; Surgeon; Testing; Therapeutic; Time; Tissues; Toxic effect; Tracer; Treatment Efficacy; Treatment Protocols; Validation; X-Ray Computed Tomography; base; clinical practice; dosimetry; experience; imaging modality; improved; in vivo; individual patient; inhibitor/antagonist; leukemia; man; novel; novel therapeutics; partial response; patient subsets; pilot trial; precision medicine; predictive test; programs; quantitative imaging; radioiodine therapy; respiratory; responders and non-responders; response; side effect; standard of care; therapy design; tool; treatment optimization; treatment strategy; tumor; unnecessary treatment; uptake

Project Summary/Abstract Precision medicine promotes matching an individualized diagnostic and treatment strategy to the functional and molecular composition of each person’s particular cancer(s). The goal of the current proposal is to apply precision medicine to the unmet need of optimal patient selection for radioiodine treatment (RAI) of metastatic thyroid cancer. Our proposal is based on measuring individual lesion dosimetry using 124I-NaI PET. The clinical problem is highly significant and the potential impact is high; distant metastases are identified in 10-15% of patients with differentiated thyroid cancer during the course of their disease, and for more than 50 years, RAI has been the standard of care for patients with structurally evident RAI-avid distant metastases. Multiple administered doses greater than 150 mCi are often required to obtain durable responses even in small volume disease. Moreover, toxicity of high-dose RAI regimens is significant, causing salivary gland damage in many patients and occasionally marrow dyscrasias, and even leukemia. In present clinical practice, dosing and patient selection are largely empirical. Thus, many patients receive repeated ineffective doses of RAI therapy, resulting in considerable morbidity without therapeutic gain. We propose a novel paradigm to select patients who stand to benefit from RAI based on an 124I PET metric that could identify patients with sufficient RAI uptake in their tumors to respond. More importantly, it would identify patients unlikely to achieve therapeutic efficacy from RAI who would be spared unnecessary treatment and the associated risks of serious side effects. We recently showed that lesional dosimetry estimates with 124I correctly identified a subset of previously non- radioiodine-avid patients who had radioiodine avidity restored by the MEK inhibitor selumetinib sufficient for structural responses to radioiodine therapy, as determined by RECIST criteria. Our proposal will dovetail with MEK and BRAF inhibitor trials and offer treatment decision criteria with which to evaluate the benefits of RAI in the context of these new medicines. If successful, this proposal will result in the development of a minimalist practical protocol that will impact all thyroid cancer patients with distant metastases being considered for additional RAI therapy, as this 124I methodology can be employed in all hospitals with a PET scanner. The objectives of our proposed approach include: 1) phantom validation of 124I quantification, which accounts for cascade coincidence gammas, respiration (for lung lesions), and partial volume corrections; 2) lesion dosimetry quantification by serial 124I PET, using the data to develop a simplified imaging paradigm to determine the achievability of a therapeutic radioiodine dose, as well as to correlate the lesional dose with structural response; 3) investigation of genomic correlates of lesion uptake and response; and 4) exploration of concurrent imaging and therapy approaches in which 124I is administered in the presence of therapeutic doses of 131I—first in phantoms and then in man to document “real-time” tumor dose.

项目摘要/摘要 精密医学促进将个性化诊断和治疗策略与功能相匹配 和每个人的特定癌症的分子组成。当前建议的目的是申请 精密药物，无法满足的最佳患者选择进行放射碘治疗（RAI）转移性治疗 甲状腺癌。我们的建议基于使用124i-Nai PET测量单个病变剂量法。临床 问题非常重要，潜在影响很高。遥远的转移在10-15％ 患有分化的甲状腺癌的患者在其疾病过程中，超过50年，RAI 对于有结构证据的远处转移的患者，一直是护理标准。多种的 通常需要大于150 MCI的剂量以获得耐用的反应 疾病。此外，大剂量RAI方案的毒性很重要，导致许多 患者，偶尔会骨髓性心理，甚至是白血病。在目前的临床实践，剂量和 患者的选择主要是经验的。这是许多患者反复接受无效剂量的RAI治疗， 导致相当大的发病率，没有治疗性增长。我们提出了一个新的范式来选择患者 他们将根据124i PET度量的RAI受益，该指标可以识别出足够的RAI的患者 吸收肿瘤以做出反应。更重要的是，它将确定患者不太可能实现治疗 RAI的效果将不受必要的治疗以及严重副作用的相关风险。 我们最近表明，具有124i的病变剂量法估计值正确鉴定 MEK抑制剂Selumetinib恢复了放射性碘的放射性二世患者足够 根据RECIST标准确定的对放射性碘治疗的结构反应。我们的建议将索引 通过MEK和BRAF抑制剂试验，并提供治疗决策标准，以评估 RAI在这些新药物的背景下。如果成功，该提议将导致发展 极简主义实用方案将影响所有甲状腺癌患者远处转移的患者 考虑进行其他RAI治疗，因为该124i方法可以在所有医院使用PET使用 扫描器。我们提出的方法的目标包括：1）幻影验证124i量化，这是 级联重合伽玛，呼吸（用于肺部病变）和部分体积校正； 2） 使用数据将简化成像范式开发到序列124i PET的病变剂量法 确定治疗性放射性碘剂量的实现，并将病变剂量与 结构反应； 3）研究病变摄取和反应的基因组相关性； 4）探索 同时进行成像和治疗方法，其中在治疗剂量的情况下进行了124i 131i-首先是幻影，然后在人类中记录“实时”肿瘤剂量。