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

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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.