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

碘难治性甲状腺癌个体化再敏化的新方法

基本信息

批准号：
10612661
负责人：
Guillem Pratx
金额：
$ 21.69万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10612661
关键词：
Aftercare Automation Biological Assay Biological Markers Biopsy Cancer Patient Cancer cell line Characteristics Clinical Clinical Management Clinical Research Development Differentiation Inducer Differentiation Therapy Disease Distant Metastasis Dose Drug Targeting Effectiveness Eligibility Determination Enrollment Future Genetic Goals Growth Image Imaging Techniques In Vitro Iodine Libraries Malignant - descriptor Malignant Neoplasms Malignant neoplasm of prostate Malignant neoplasm of thyroid Measures Metastatic Prostate Cancer Modeling Molecular Molecular Analysis Mutation Neoplasm Metastasis Neuroendocrine Tumors Operative Surgical Procedures Organoids Outcome Papillary thyroid carcinoma Patients Performance Pharmaceutical Preparations Pharmacotherapy Phenotype Phosphotransferases Pilot Projects Primary Neoplasm Process Prognosis Radiation Radioactive Iodine Radioisotopes Radionuclide Imaging Radiopharmaceuticals Rapid screening Recommendation Refractory Refractory Disease Reproducibility Resected Resolution Sampling Scanning Schedule Specimen Technology Testing Therapeutic Therapeutic Agents Toxic effect Translating Treatment Protocols Tumor Tissue Unresectable cancer cell detection limit disease heterogeneity effective therapy high throughput screening improved in vivo individualized medicine kinase inhibitor neoplastic cell neuroendocrine cancer novel nuclear imaging patient screening pharmacologic predictive marker radioiodine therapy refractory cancer screening side effect standard of care survival outcome three dimensional cell culture thyroid neoplasm tumor uptake

项目摘要

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.

抽象的患有远处转移或无法切除疾病的甲状腺癌患者长期治疗的可能性很小生存。放射性碘（RAI）可以特异性、系统性地根除恶性甲状腺癌细胞，已通过转移扩散至全身。然而，5-15% 的甲状腺癌患者最终进展为 RAI 难治性状态，这是所有甲状腺癌病例中预后最差的。难治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，就会发生这种情况。最近的临床研究已经表明激酶抑制剂和其他药物可以通过难治性肿瘤的再分化来逆转这种效应细胞，从而恢复集中 RAI 所需的细胞机制。然而，这种再差异化策略优化和临床部署仍然具有挑战性。造成这种情况的原因包括患者数量少合格、疾病的异质性、靶向激酶疗法的毒性以及缺乏稳健的研究生物标志物。该项目将开发甲状腺乳头状癌类器官来研究和个体化使用再分化剂可恢复 RAI 难治性患者的 RAI 摄取。在第一个目标中，我们开发了一部小说自动化和高通量测定，用于测量数千个肿瘤类器官培养物中 RAI 的摄取。这将优化检测以实现特定的性能目标，包括通量、线性、检测限、和再现性。在第二个目标中，我们将在一项有 10 名患者参与的小型试点研究中演示该检测方法。这肿瘤类器官组包括 RAI 敏感型和难治性疾病，将用于筛选基于 RAI 摄取的相关药物库。使用该方法，我们将优化剂量和时间安排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副作用激酶抑制剂的不良副作用。