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

项目摘要/摘要 精准医学促进个性化诊断和治疗策略与功能 以及每个人特定癌症的分子组成(S)。当前提案的目标是应用 精准医学满足转移性肿瘤放射性碘治疗(RAI)最佳患者选择的需求 甲状腺癌。我们的建议是基于使用124I-NaI PET测量单个病变的剂量。临床部 问题非常严重，潜在影响很大；10%-15%的人发现有远处转移 分化型甲状腺癌患者在他们的病程中，超过50年来，RAI 一直是结构明显的RAI-Avid远处转移患者的标准护理。多重 即使在小容量的情况下，通常也需要超过150mci的剂量才能获得持久的反应 疾病。此外，大剂量RAI方案的毒性是显著的，导致许多人的唾液腺损伤。 患者偶尔还会患上骨髓萎缩，甚至白血病。在目前的临床实践中，剂量和 患者选择在很大程度上是经验性的。因此，许多患者接受重复无效剂量的RAI治疗， 导致相当大的发病率而不能获得治疗收益。我们提出了一种新的选择患者的范例 谁将受益于基于124I PET指标的RAI，该指标可以识别具有足够RAI的患者 在他们的肿瘤中摄取做出反应。更重要的是，它将识别出不太可能实现治疗的患者 RAI的疗效将避免不必要的治疗和相关的严重副作用风险。 我们最近表明，用124I进行的皮损剂量学估计正确地识别了以前没有的子集 经MEK抑制剂塞鲁米替尼充分恢复放射性碘亲和力的放射性碘摄取者 根据RECIST标准确定的对放射性碘治疗的结构反应。我们的建议将会相吻合 与MEK和BRAF抑制剂试验，并提供治疗决策标准，以评估 RAI在这些新药的背景下。如果成功，这项提议将导致开发一种 将影响所有有远处转移的甲状腺癌患者的最低限度实用方案 考虑进行额外的RAI治疗，因为这种124I方法可以在所有有PET的医院使用 扫描仪。我们提出的方法的目标包括：1)124I量化的模体验证，这是 考虑了级联符合伽玛、呼吸(对于肺部病变)和部分体积校正；2) 使用系列124I PET对病变剂量进行量化，使用数据开发简化的成像范例 确定治疗性放射性碘剂量的可得性，以及皮损剂量与 结构反应；3)研究病变摄取和反应的基因组相关性；以及4)探索 在治疗剂量存在的情况下同时给予124I的成像和治疗方法 131I-首先在幻影中，然后在人类中记录“实时”的肿瘤剂量。

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.