A Novel Assay to Individualize Resensitization of Iodine-Refractory Thyroid Cancer

摘要 有远处转移或不能切除的甲状腺癌患者， 生存放射性碘（RAI）可以特异性地和全身性地根除恶性甲状腺癌细胞， 通过转移扩散到全身然而，5-15%的甲状腺癌患者最终 进展为RAI难治状态，其在所有甲状腺癌病例中预后最差。难治性疾病 当甲状腺肿瘤细胞失去其吸收和浓缩RAI的先天能力时发生。近期临床研究 激酶抑制剂和其他药物可以通过使难治性肿瘤重新分化来逆转这种效应 细胞，从而恢复所需的细胞机器集中RAI。然而，这种再分化策略 在临床上优化和部署仍然具有挑战性。原因包括患者数量少 合格，疾病的异质性，靶向激酶治疗的毒性，以及缺乏强大的 生物标志物。该项目将开发乳头状甲状腺癌类器官，以研究和个性化使用 再分化剂，以恢复RAI难治性患者的RAI摄取。在第一个目标中，我们开发了一个新的 自动化和高通量测定来测量数千种肿瘤类器官培养物中的RAI摄取。的 将对检测试剂盒进行优化，以达到特定的性能目标，包括通量、线性、检测限， 和再现性。在第二个目标中，我们将在10名患者的小型试点研究中证明该测定。的 一组肿瘤类器官，包括RAI敏感性和难治性疾病，将用于筛选 基于RAI摄取的相关药物库。使用该方法，我们将优化给药和调度 治疗的最终目标是个体化治疗，以最大限度地提高疗效，同时最大限度地减少 激酶抑制剂的副作用。

Abstract Thyroid cancer patients with distant metastases or unresectable disease have poor likelihood of long-term survival. Radioactive iodine (RAI) can specifically and systemically eradicate malignant thyroid cancer cells that have spread throughout the body through metastasis. However, 5-15% of all thyroid cancer patients eventually progress to RAI-refractory status, which has the poorest prognosis of all thyroid cancer cases. Refractory disease occurs when thyroid tumor cells lose their innate ability to take up and concentrate RAI. Recent clinical studies have shown that kinase inhibitors and other drugs can reverse this effect by redifferentiating refractory tumor cells, thus restoring the cellular machinery required to concentrate RAI. However, this redifferentiation strategy remains challenging to optimize and deploy clinically. The reasons for this include the small number of patients eligible, the heterogeneity of the disease, the toxicity of targeted kinase therapies, and the lack of robust biomarkers. This project will develop papillary thyroid carcinoma organoids to study and individualize the use of redifferentiation agents to restore RAI uptake in RAI-refractory patients. In the first Aim, we develop a novel automated and high-throughput assay to measure RAI uptake in thousands of tumor organoid cultures. The assay will be optimized to achieve specific performance goals, including throughput, linearity, limit of detection, and reproducibility. In the second Aim, we will demonstrate the assay in a small pilot study of 10 patients. The panel of tumor organoids, which will include both RAI-sensitive and refractory disease, will be used to screen a library of relevant drugs on the basis of RAI uptake. Using the approach, we will optimize dosing and scheduling of the treatments towards the eventual goal of individualizing therapy to maximize efficacy while minimizing the adverse side effects of kinase inhibitors.