Development of a multi-analyte diagnostic assay to improve the risk stratification of indeterminate thyroid nodules

开发多分析物诊断测定法以改善不确定甲状腺结节的风险分层

• 批准号: 10545522
• 负责人: GISELLE M KNUDSEN
• 金额: $ 87.12万
• 依托单位: ALAUNUS BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10545522
• 关键词: Address; Affect; Antibodies; Autopsy; Award; Benchmarking; Benign; Biological; Biological Assay; Biological Markers; Biological Sciences; Biopsy; Biopsy Specimen; Categories; Cells; Clinic; Clinical; Clinical Management; Collaborations; Contracts; Cooperative Human Tissue Network; Cytology; DNA Sequence Alteration; Data; Detection; Development; Diagnosis; Diagnostic; Diagnostic Imaging; Diagnostic tests; Disease; Documentation; Early Diagnosis; Excision; Feasibility Studies; Fine needle aspiration biopsy; Fluorogenic Substrate; Frequencies; Genetic Risk; Genomics; Goals; Gold; Guidelines; Image; Indiana; Industry Standard; Institutional Review Boards; Investigation; Laboratories; Lesion; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of thyroid; Measures; Molecular; Molecular Analysis; Monitor; Nodule; Nucleotides; Operative Surgical Procedures; Pathologic; Pathology; Patient risk; Patients; Peptide Hydrolases; Performance; Persons; Phase; Predictive Value; Prevalence; Prospective cohort; Proteins; Proteolysis; Proteomics; Readiness; Reporting; Resected; Retrospective cohort; Risk; Risk Marker; Sampling; Science; Scientific Advances and Accomplishments; Sensitivity and Specificity; Source; Specificity; Technology; Testing; Thyroid Gland; Thyroid Nodule; Thyroidectomy; Tissue Sample; Tissues; Ultrasonography; United States; Universities; Unnecessary Surgery; Validation; Work; base; biobank; biomarker discovery; cancer invasiveness; clinical center; clinical decision-making; clinical practice; cohort; commercialization; cost; detection limit; diagnostic accuracy; diagnostic assay; diagnostic biomarker; diagnostic tool; enzyme activity; improved; innovation; mortality; novel marker; patient stratification; precision medicine; premalignant; prognostic; programs; prospective; rapid test; risk stratification; standard of care; tool; ultrasound; validation studies

Abstract Widespread use of sensitive imaging in clinical practice has resulted in incidental thyroid nodules being discovered with increasing frequency, creating a unique opportunity to detect and remove lesions at early stages of malignancy. The majority of these incidental nodules remain benign and asymptomatic, but 10-20% are found to be malignant on surgical excision, resulting in a critical need for improved diagnostics, as 75% of patients currently undergo unnecessary thyroidectomies to remove benign nodules. The current standard of care includes collecting a tissue biopsy by ultrasound-guided fine needle aspiration: these samples are tested by cytology, which looks for aberrant cells, and for genetic risk markers. These diagnostic tests are characterized by poor specificity, and a third of all tested nodules are still classified as indeterminate and need to be resected for a pathological diagnosis. We originally hypothesized that dysregulated proteolysis, a type of enzyme activity that is a hallmark of invasive cancer, might yield discriminating levels of activity in FNA tissue from benign and malignant nodules. In Phase I work, we leveraged the Alaunus Biosciences, Inc. diagnostic pipeline, a platform that allows innovative proteomics-based biomarker discovery, to identify and characterize a set of protease activities (functional markers) that are significantly increased in malignant nodules. We then developed fluorogenic substrate assays to monitor these activities using small volumes of biological samples. In parallel, we also discovered additional mass-based markers that can be measured with standard antibody-based assays. Our investigational multi-analyte diagnostic assay has the potential to differentiate malignant from benign thyroid tissue with sensitivity and specificity >90%. In this Phase II proposal, we aim to perform technical and clinical validation studies required to advance the assay to readiness for clinical use in the early diagnosis of indeterminate thyroid nodules. In Aim 1, we will benchmark the clinical utility of our selected protein and functional biomarkers in surgical tissue to evaluate scoring, establish diagnostic thresholds, and report on key assay parameters. In Aim 2, we will perform a comprehensive technical assessment of the laboratory performance of the assay to satisfy industry standards. In Aim 3, we will create an independent cohort of FNA tissue samples, through our IRB- approved biobanking efforts at UCSF, UCLA and IU, to be used for a robust prospective validation of the clinical usefulness of the assay. Our goal is to develop a rapid assay that improves patient stratification over current standard diagnostic markers, guides clinical decision-making to avoid unnecessary surgical intervention, and transforms the clinical management of these challenging lesions.

抽象的 在临床实践中广泛使用敏感成像导致了偶然的甲状腺结节 被频率越来越大，创造了一个独特的机会来检测和删除 恶性肿瘤的早期病变。这些附带结节中的大多数仍然是良性的， 无症状，但发现10-20％的手术切除是恶性的，导致了急需 为了改善诊断，由于目前有75％的患者经历了不必要的甲状腺切除术 删除良性结节。当前的护理标准包括通过 超声引导的细针抽吸：这些样品通过细胞学测试，寻找 异常细胞，用于遗传风险标记。这些诊断测试的特征是差 特异性和所有测试结节的三分之一仍被归类为不确定的，需要为 切除用于病理诊断。我们最初假设失调的蛋白水解，A 酶活性的类型是侵入性癌症的标志，可能会产生区分水平 来自良性和恶性结节的FNA组织的活性。在第一阶段的工作中，我们利用了Alaunus Biosciences，Inc。诊断管道，该平台允许基于创新的蛋白质组学生物标志物 发现，识别和表征一组蛋白酶活动（功能标记） 恶性结节显着增加。然后，我们开发了荧光底物测定到 使用少量的生物样品监测这些活动。同时，我们也发现了 可以用标准抗体测定法测量的其他基于质量标记。我们的 研究性多分析物诊断测定有可能区分恶性与良性 甲状腺组织的灵敏度和特异性> 90％。在此第二阶段提案中，我们旨在执行 需要提高测定的技术和临床验证研究，以准备临床使用 不确定甲状腺结节的早期诊断。在AIM 1中，我们将基准进行临床实用程序 我们选择的手术组织中选择的蛋白质和功能性生物标志物来评估评分，建立 诊断阈值，并报告关键测定参数。在AIM 2中，我们将执行 对实验室的实验室性能的全面技术评估以满足行业 标准。在AIM 3中，我们将通过我们的IRB创建独立的FNA组织样品队列 在UCSF，UCLA和IU批准的生物库，用于强大的预期验证 测定的临床实用性。我们的目标是开发一种快速测定，以改善患者 对当前标准诊断标记的分层，指导临床决策以避免 不必要的手术干预，并改变了这些具有挑战性的临床管理 病变。