Validation of predictive liquid biomarkers for patients with metastatic prostate cancer

转移性前列腺癌患者预测液体生物标志物的验证

• 批准号: 10214744
• 负责人: Andrew J Armstrong
• 金额: $ 19.14万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10214744
• 关键词: AR gene; Acetates; Address; Adenocarcinoma; Aftercare; Androgen Receptor; Appearance; Area; Biological Assay; Biological Markers; Biological Response Modifier Therapy; Biomedical Engineering; Biopsy; Blood; Blood Cells; Blood Circulation; CLIA certified; Cancer Center; Cancer Patient; Categories; Cells; Cellular Assay; Centrifugation; Certification; Clinical; Clinical Research; Clinical Trials; Clonal Expansion; Collaborations; DNA; Data Analyses; Detection; Development; Diagnostic; Diagnostic radiologic examination; Disease; Disease Resistance; Early Diagnosis; Early identification; Enhancers; Ensure; Evaluation; Evolution; Exclusion; Exposure to; Failure; Foundations; Frequencies; Future; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic Transcription; Goals; Histologic; Hygiene; Institution; Laboratories; Left; Ligand Binding Domain; Liquid substance; Liver; Magnetism; Malignant Neoplasms; Malignant neoplasm of prostate; Measurement; Memorial Sloan-Kettering Cancer Center; Messenger RNA; Metastatic Prostate Cancer; Methods; Molecular; Mutation; Neoplasm Circulating Cells; Neuroendocrine Prostate Cancer; Neuroendocrine Tumors; Output; Patient Care; Patients; Performance; Population; Preparation; Probability; Process; Prognosis; Progression-Free Survivals; Prospective Studies; Protein Analysis; Provenge; RNA; RNA Splicing; Radium; Randomized Clinical Trials; Reagent; Receptor Signaling; Recommendation; Research Personnel; Resistance; Resistance development; Risk; Sampling; Site; Specificity; Surface Properties; Surface Tension; System; Systematic Bias; Technology; Testing; Therapeutic; Time; Tissues; Tube; Universities; Validation; Variant; Wisconsin; abiraterone; advanced prostate cancer; base; bone; cancer biomarkers; cancer cell; castration resistant prostate cancer; chemotherapy; clinically relevant; cohort; diagnostic accuracy; drug development; hormone therapy; improved; inhibitor/antagonist; liquid biopsy; lymph nodes; men; novel diagnostics; novel therapeutics; optimal treatments; particle; patient biomarkers; patient subsets; precision medicine; predictive marker; prognostic; prognostic of survival; prognostic value; prospective; research clinical testing; resistance mechanism; response; success; targeted treatment; taxane; therapy resistant; tool; treatment strategy; treatment stratification; tumor; virtual

Project Summary/Abstract The University of Wisconsin Carbone Cancer Center (UWCCC), Duke University and Memorial Sloan Kettering Cancer Center (MSKCC) seek support for establishing the analytical and clinical validity of a Circulating Tumor Cell (CTC) biomarker assay via the UH2/UH3 mechanism. This biomarker assay will evaluate a gene expression signature of treatment resistant, castration-resistant prostate cancer (CRPC). While many patients with prostate cancer benefit from Androgen Receptor Signaling Inhibitors (ARSIs), a subset of patients do not respond to this class of treatments while nearly all others develop resistance within 1-2 years. Identified mechanisms of resistance include development of Neuroendocrine Prostate Cancer (NEPC) and expression of Androgen Receptor Splicing Variants (AR-Vs). Early detection of NEPC or AR-Vs as drivers of treatment resistant prostate cancer would eliminate the need to wait for clinical manifestations of resistance, accelerating the time to administration of more suitable therapy and increasing survival. While precision medicine approaches are increasing in popularity and reliability, their ultimate capacity to improve patient care hinges on their diagnostic accuracy. Realization of a clinically relevant assay requires thorough analytical and clinical evaluation, and while many biomarker assays have successfully demonstrated analytical performance, failure to address clinical utility has left many unable to improve on existing diagnostics. By focusing our efforts on evaluation of both analytical and clinical validity, we aim to provide diagnostic accuracy in assessing an expression of NEPC and AR-Vs, building a necessary foundation for future clinical trials. To that end, we have optimized a multi-plexed gene expression assay on CTCs, that identifies these two major categories of resistance to ARSIs. This assay has shown promising initial results in a preliminary cohort of patients with aggressive CRPC. Optimization of this assay has taken into consideration the rarity of CTCs and the diversity of other blood cells in circulation; ensuring efficient RNA extraction, probe specificity, and appropriate data interpretation. The manipulation and retention of rare cells is enabled by our Exclusion-based Sample Preparation (ESP) technology, wherein centrifugation and wash steps are eliminated. This automated and commercially available platform, also called the Gilson ExtractMax, offers minimal user variability, thus maximizing precision. Our collaboration with Dr. Kaitlin Sundling at the Wisconsin State Lab of Hygiene, a CAP- approved clinical testing laboratory, provides expert oversight for planning and execution of analytical validation. In collaboration with Dr. Andrew Armstrong, Dr. Susan Halabi and Dr. Dana Rathkopf, we have assembled a team of clinical researchers and biostatisticians to rapidly validate this multi-plexed biomarker in a prospective study. This RNA-based CTC assay shows potential for identifying treatment resistant prostate cancer in preliminary studies of patients and is thus poised for success in both analytical and clinical validation.

项目概要/摘要 威斯康星大学卡本癌症​​中心 (UWCCC)、杜克大学和纪念斯隆凯特琳大学 癌症中心 (MSKCC) 寻求支持以建立循环肿瘤的分析和临床有效性 通过 UH2/UH3 机制进行细胞 (CTC) 生物标志物测定。该生物标志物测定将评估基因表达 治疗抵抗性、去势抵抗性前列腺癌（CRPC）的特征。 虽然许多前列腺癌患者受益于雄激素受体信号抑制剂 (ARSI)，但其中一个子集 的患者对此类治疗没有反应，而几乎所有其他患者都会在 1-2 年内产生耐药性。 已确定的耐药机制包括神经内分泌前列腺癌 (NEPC) 的发展和 雄激素受体剪接变体（AR-V）的表达。及早发现 NEPC 或 AR-V 作为驱动因素 治疗耐药性前列腺癌将消除等待耐药性临床表现的需要， 加快实施更合适治疗的时间并提高生存率。 虽然精准医学方法越来越受欢迎和可靠，但它们的最终能力 改善患者护理取决于诊断的准确性。实现临床相关测定需要 彻底的分析和临床评估，虽然许多生物标志物测定已成功证明 分析性能、未能解决临床实用性问题导致许多人无法改进现有的诊断方法。 通过集中精力评估分析和临床有效性，我们的目标是提供诊断准确性 评估 NEPC 和 AR-V 的表达，为未来的临床试验奠定必要的基础。 为此，我们优化了 CTC 的多重基因表达测定，可识别这两个主要的 ARSI 耐药性的类别。该测定在初步队列中显示出有希望的初步结果 侵袭性 CRPC 患者。该测定的优化考虑了 CTC 的稀有性和 循环中其他血细胞的多样性；确保有效的 RNA 提取、探针特异性和 适当的数据解释。通过我们基于排除的方法，可以对稀有细胞进行操作和保留 样品制备 (ESP) 技术，其中消除了离心和洗涤步骤。这个自动化的 商用平台，也称为 Gilson ExtractMax，提供最小的用户可变性，因此 最大限度地提高精度。我们与威斯康星州立卫生实验室 (CAP-) 的 Kaitlin Sundling 博士合作 经批准的临床测试实验室，为分析验证的规划和执行提供专家监督。 我们与 Andrew Armstrong 博士、Susan Halabi 博士和 Dana Rathkopf 博士合作，组建了 由临床研究人员和生物统计学家组成的团队将前瞻性地快速验证这种多重生物标志物 学习。这种基于 RNA 的 CTC 检测显示出识别治疗耐药性前列腺癌的潜力 患者的初步研究，因此有望在分析和临床验证方面取得成功。