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

项目总结/摘要 精准医疗促进个性化诊断和治疗策略与功能性 和每个人特定癌症的分子组成。当前提案的目标是适用于 精确医学，以满足放射性碘治疗（RAI）转移性癌的最佳患者选择的需求 甲状腺癌我们的建议是基于使用124 I-NaI PET测量个体病变剂量学。临床 这个问题非常重要，潜在的影响也很大;在10-15%的患者中发现了远处转移。 分化型甲状腺癌患者在他们的疾病过程中，并超过50年，RAI 已成为具有结构上明显的RAI-亲和性远处转移的患者的标准治疗。多 即使在小体积中也经常需要大于150 mCi的给药剂量来获得持久的反应 疾病此外，高剂量RAI方案的毒性是显著的，在许多患者中引起唾液腺损伤。 患者和偶尔骨髓恶液质，甚至白血病。在目前的临床实践中，给药和 病人的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没有治疗效果。我们提出了一种新的模式来选择病人 基于124 I PET指标，可以识别具有足够RAI的患者， 来产生反应。更重要的是，它将识别出不太可能获得治疗的患者， 从RAI谁将免除不必要的治疗和严重副作用的相关风险的疗效。 我们最近表明，用124 I进行的损伤剂量测定估计正确地识别了以前未发现的一个亚组。 MEK抑制剂司美替尼恢复放射性碘亲合力的放射性碘亲合力患者 根据RECIST标准确定的放射性碘治疗的结构反应。我们的建议将相互吻合 MEK和BRAF抑制剂试验，并提供治疗决策标准，以评估 在这些新药的背景下。如果成功，这一建议将导致发展一个 最低限度的实用方案，将影响所有远处转移的甲状腺癌患者， 考虑用于额外的RAI治疗，因为这种124 I方法可用于所有具有PET的医院。 扫描仪我们提出的方法的目标包括：1）124 I定量的体模验证， 考虑级联符合伽马、呼吸（肺部病变）和部分容积校正; 2） 通过连续124 I PET进行病变剂量定量，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接受性，以及将损伤剂量与 结构反应; 3）研究病变吸收和反应的基因组相关性;以及4）探索 在存在治疗剂量的情况下给予124 I的同时成像和治疗方法 131 I-首先在幻影，然后在人记录“实时”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.