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.

摘要 在临床实践中广泛使用敏感成像已导致偶发甲状腺结节。 被发现的频率越来越高，创造了独特的机会来检测和删除 恶变早期的病变。这些偶发结节中的大多数仍然是良性的和 无症状，但在手术切除时发现10-20%是恶性的，因此迫切需要 为了改善诊断，因为75%的患者目前接受了不必要的甲状腺切除术，以 清除良性结节。目前的护理标准包括通过以下方式收集组织活检 超声引导细针抽吸：这些样本通过细胞学检测，以寻找 异常细胞，以及遗传风险标记。这些诊断测试的特点是质量不佳 特异性，所有检测的结核中有三分之一仍被归类为不确定的，需要 切除做病理诊断。我们最初的假设是，失调的蛋白质分解，一种 作为浸润性癌症标志的酶活性类型，可能会产生区分水平的 良、恶性结节的FNA组织中的活性。在第一阶段的工作中，我们利用ALaunus Biosciences，Inc.，一个允许创新的基于蛋白质组学的生物标记物的平台 发现，以确定和表征一组蛋白酶活性(功能标记)，这些活性 在恶性结节中显著增加。然后我们开发了荧光底物分析方法来 使用少量的生物样本监测这些活动。与此同时，我们还发现 额外的基于质量的标记物，可以用标准的基于抗体的分析方法进行测量。我们的 调查性多分析诊断分析有可能区分良恶性 甲状腺组织的敏感度和特异度为90%。在此第二阶段提案中，我们的目标是执行 需要进行技术和临床验证研究，以使该分析方法准备好在 不明原因甲状腺结节的早期诊断。在目标1中，我们将对临床应用进行基准测试 我们精选的手术组织中的蛋白质和功能生物标记物来评估评分，建立 诊断阈值，并报告关键的分析参数。在目标2中，我们将执行 对实验室性能进行全面的技术评估，以满足行业的要求 标准。在目标3中，我们将通过我们的IRB创建一个独立的FNA组织样本队列- 加州大学旧金山分校、加州大学洛杉矶分校和伊利诺伊州立大学批准的生物库工作，用于对 这项检测的临床实用性。我们的目标是开发一种快速检测方法，以改善患者状况 分层超越当前标准的诊断标记物，指导临床决策避免 不必要的手术干预，并转变了这些具有挑战性的临床管理 损伤。