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

基本信息

批准号：
9326954
负责人：
JOHN L HUMM
金额：
$ 69.53万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-05 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9326954
关键词：
Ablation Adverse effects 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 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 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 programs quantitative imaging radioiodine therapy radiosensitive respiratory responders and non-responders response standard of care therapy design tool treatment strategy tumor unnecessary treatment uptake

项目摘要

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.

项目概要/摘要精准医疗促进个体化诊疗策略与功能相匹配以及每个人特定癌症的分子组成当前提案的目标是应用。精准医学，以满足转移性放射性碘治疗 (RAI) 最佳患者选择的未满足需求我们的建议基于使用 124I-NaI PET 测量个体病变剂量。问题非常严重，潜在影响很大；10-15% 的患者发现了远处转移；分化型甲状腺癌患者在其病程中，并且 50 多年来，RAI 已成为结构明显的 RAI 多发性远处转移患者的护理标准。即使剂量很小，通常也需要大于 150 mCi 的给药剂量才能获得持久的反应此外，高剂量 RAI 疗法的毒性很大，会导致许多人唾液腺损伤。在目前的临床实践中，患者有时会出现骨髓恶液质，甚至白血病。患者的选择很大程度上取决于经验，因此，许多患者接受了重复无效剂量的 RAI 治疗。导致相当大的发病率而没有治疗效果，我们提出了一种新的范例来选择患者。谁将从基于 124I PET 指标的 RAI 中受益，该指标可以识别具有足够 RAI 的患者更重要的是，它将识别出不太可能实现治疗的患者。 RAI 的疗效使他们可以避免不必要的治疗和严重副作用的相关风险。我们最近表明，使用 124I 进行的病变剂量测定正确地识别了以前非通过 MEK 抑制剂塞美替尼恢复放射性碘亲合力的患者根据 RECIST 标准确定的对放射性碘治疗的结构反应，我们的建议将与之吻合。进行 MEK 和 BRAF 抑制剂试验，并提供治疗决策标准来评估以下药物的益处 RAI 在这些新药的背景下如果成功，该提案将导致一种药物的开发。简约实用的方案将影响所有患有远处转移的甲状腺癌患者考虑进行额外的 RAI 治疗，因为这种 124I 方法可在所有拥有 PET 的医院采用我们提出的方法的目标包括：1）124I 定量的幻影验证，其中考虑级联重合伽马、呼吸（针对肺部病变）和部分体积校正2) 通过串行 124I PET 进行病变剂量测定量化，使用数据开发简化的成像范例确定治疗放射性碘剂量的可实现性，以及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）探索并行成像和治疗方法，其中在治疗剂量存在的情况下施用 124I 131I——首先在模型中，然后在人体中记录“实时”肿瘤剂量。