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: 10684875
• 负责人: GISELLE M KNUDSEN
• 金额: $ 69.6万
• 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/10684875
• 关键词: Address; Affect; Antibodies; Autopsy; Benchmarking; Benign; Biological; Biological Assay; Biological Markers; Biological Sciences; Biopsy; Biopsy Specimen; Categories; Cells; Classification; 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; Guidelines; Image; Indiana; Industry Standard; Institutional Review Boards; 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; 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; technology validation; 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 敏感成像在临床实践中的广泛使用导致了甲状腺结节的偶然发生 被发现的频率越来越高，创造了独特的检测和删除机会 恶性肿瘤早期阶段的病变。大多数这些偶发结节仍然是良性的 无症状，但手术切除时发现 10-20% 为恶性，导致迫切需要 改善诊断，因为目前 75% 的患者接受了不必要的甲状腺切除术 去除良性结节。目前的护理标准包括通过以下方式收集组织活检： 超声引导下的细针抽吸：这些样本经过细胞学检测，寻找 异常细胞，以及遗传风险标记。这些诊断测试的特点是效果不佳 特异性，所有测试结节的三分之一仍被归类为不确定，需要 切除以进行病理诊断。我们最初假设蛋白水解失调， 作为侵袭性癌症标志的酶活性类型，可能会产生可区分的水平 良性和恶性结节 FNA 组织中的活性。在第一阶段的工作中，我们利用了 Alaunus Biosciences, Inc. 诊断管道，一个允许基于蛋白质组学的创新生物标志物的平台 发现，识别和表征一组蛋白酶活性（功能标记） 恶性结节明显增多。然后我们开发了荧光底物检测 使用少量生物样本监测这些活动。与此同时，我们还发现 可以使用基于标准抗体的测定法进行测量的其他基于质量的标记。我们的 研究中的多分析物诊断分析有可能区分恶性与良性 甲状腺组织的敏感性和特异性 >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，以推进该测定为临床使用做好准备 不确定性甲状腺结节的早期诊断。在目标 1 中，我们将对以下药物的临床效用进行基准测试： 我们在手术组织中选择的蛋白质和功能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。在目标 2 中，我们将执行 对化验实验室性能进行全面技术评估，以满足行业需求 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 批准了加州大学旧金山分校、加州大学洛杉矶分校和印第安纳大学的生物样本库工作，用于对 该测定的临床用途。我们的目标是开发一种快速检测方法来改善患者的症状 对当前标准诊断标志物进行分层，指导临床决策以避免 不必要的手术干预，并改变这些具有挑战性的临床管理 病变。