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

摘要 有远处转移或不能切除疾病的甲状腺癌患者长期生存的可能性很低。 生死存亡。放射性碘(RAI)可以特异性和系统地根除恶性甲状腺癌细胞 已经通过转移扩散到全身。然而，最终有5%-15%的甲状腺癌患者 进展到RAI难治状态，这是所有甲状腺癌病例中预后最差的。顽固性疾病 当甲状腺肿瘤细胞失去吸收和浓缩RAI的先天能力时发生。近期临床研究 已经表明，激酶抑制剂和其他药物可以通过重新分化难治性肿瘤来逆转这一效应 细胞，从而恢复集中RAI所需的细胞机械。然而，这种再分化战略 在临床上优化和部署仍然具有挑战性。这其中的原因包括患者数量较少。 合格的，疾病的异质性，靶向激酶疗法的毒性，以及缺乏强大的 生物标志物。本项目将开发甲状腺乳头状癌的有机体来研究和个体化使用 RAI难治性患者恢复RAI摄取的再分化药物。在第一个目标中，我们开发了一部小说 自动化和高通量检测数千种肿瘤器官培养中RAI的摄取。这个 将对分析进行优化，以实现特定的性能目标，包括吞吐量、线性、检测限、 和再现性。在第二个目标中，我们将在一项对10名患者进行的小型先导性研究中演示该检测方法。这个 包括RAI敏感疾病和难治性疾病在内的肿瘤有机化合物小组将被用于筛选 以RAI摄取为基础的相关药物文库。使用这种方法，我们将优化配药和调度 治疗的最终目标是个体化治疗，以最大限度地提高疗效，同时将 激酶抑制剂的不良副作用。

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.