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: 10840022
• 负责人: Andrew J Armstrong
• 金额: $ 36.35万
• 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 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10840022
• 关键词: AR gene; Acceleration; Acetates; Address; Adenocarcinoma; Aftercare; Androgen Receptor; Appearance; Area; Biological; Biological Assay; Biological Markers; Biomedical Engineering; Biopsy; Blood; Blood Cells; CLIA certified; Cancer Center; Cancer Patient; Categories; Cells; Cellular Assay; Centrifugation; Circulation; Clinical; Clinical Research; Clinical Trials; Clonal Expansion; Collaborations; DNA; Data Analyses; Detection; Development; Diagnostic; 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; 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; bone; cancer biomarkers; cancer cell; castration resistant prostate cancer; chemotherapy; clinically relevant; cohort; detection method; diagnostic accuracy; diagnostic tool; drug development; enzalutamide; hormone therapy; improved; inhibitor; 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; radiological imaging; randomized, clinical trials; 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.

项目摘要/摘要 威斯康星大学碳癌癌症中心（UWCCC），杜克大学和纪念斯隆·凯特林 癌症中心（MSKCC）寻求支持建立循环肿瘤的分析和临床有效性 细胞（CTC）生物标志物通过UH2/UH3机制。该生物标志物测定将评估基因表达 抗治疗，耐castration的前列腺癌（CRPC）的签名。 尽管许多患有前列腺癌的患者受益于雄激素受体信号传导抑制剂（ARSI），但 大量患者对这类治疗没有反应，而几乎所有其他患者在1 - 2年内都会产生抗药性。 确定的抗药性机制包括神经内分泌前列腺癌（NEPC）和 雄激素受体剪接变体（AR-VS）的表达。早期发现NEPC或AR-VS作为驱动程序 耐药前列腺癌将消除等待抗药性临床表现的需要， 加速给予更合适的治疗和增加生存时间的时间。 虽然精确医学方法的流行和可靠性越来越高，但它们的最终能力 改善患者护理取决于其诊断准确性。实现临床相关测定需要 彻底的分析和临床评估，尽管许多生物标志物测定已成功证明 分析性能，无法解决临床公用事业，使许多人无法改善现有诊断。 通过将我们的精力集中在评估分析和临床有效性上，我们旨在提供诊断准确性 在评估NEPC和AR-VS的表达时，为将来的临床试验奠定了必要的基础。 为此，我们在CTC上优化了多重基因表达测定法，该测定标识了这两个主要的 抵抗Arsis的类别。该测定在初步的队列中显示出令人鼓舞的初始结果 具有侵略性CRPC的患者。该测定法的优化已经考虑到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。我们的排除基于排除 样品制备（ESP）技术，消除了离心和洗涤步骤。这是自动化的 以及商业可用的平台，也称为Gilson Extractmax，提供了最小的用户可变性，因此 最大化精度。我们与威斯康星州卫生实验室的Kaitlin Sundling博士的合作，这是一个上限 批准的临床测试实验室，为计划和执行分析验证提供了专家监督。 与安德鲁·阿姆斯特朗（Andrew Armstrong）博士，苏珊·哈拉比（Susan Halabi）博士和达娜·拉斯科普（Dana Rathkopf）博士合作，我们组装了一个 临床研究人员和生物统计学家团队在潜在的 学习。这种基于RNA的CTC测定法显示了鉴定耐药性前列腺癌的潜力 对患者的初步研究，因此有望在分析和临床验证方面取得成功。