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 威斯康星大学碳骨癌中心(UWCCC)、杜克大学和斯隆·凯特林纪念馆 癌症中心(MSKCC)寻求支持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)生物标志物分析。这一生物标志物分析将评估一个基因的表达 耐治疗、耐去势前列腺癌(CRPC)的签名。 虽然许多前列腺癌患者受益于雄激素受体信号抑制药(Arsis)，但它的一个子集 的患者对这类治疗没有反应，而几乎所有其他患者在1-2年内产生抗药性。 已确定的耐药机制包括发生神经内分泌前列腺癌(NEPC)和 雄激素受体剪接变异体(AR-vs)的表达。早期发现NEPC或AR-V作为驱动因素 耐药前列腺癌将不再需要等待耐药的临床表现， 加快进行更合适的治疗的时间，提高存活率。 虽然精准医疗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他们诊断的准确性。实现临床上相关的检测需要 彻底的分析和临床评估，虽然许多生物标志物分析已经成功地证明 分析性能，未能解决临床实用问题，使许多人无法改进现有的诊断。 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的准确性 在评估NEPC和AR-vs的表达方面，为未来的临床试验建立必要的基础。 为此，我们优化了CTCs上的多重基因表达分析，该分析鉴定了这两个主要的 对Arsis的抗性类别。这项测试在初步队列中显示了有希望的初步结果。 侵袭性CRPC患者。该方法的优化考虑了CTCs和CTC的稀有性 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。稀有细胞的操作和保留是通过我们基于排除的 样品制备(ESP)技术，省去了离心和洗涤步骤。这是自动的 商业上可用的平台，也被称为Gilson ExtractMax，提供最小的用户变异性，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的Kaitlin Sundling博士合作，这是一项CAP- 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。 在安德鲁·阿姆斯特朗博士、苏珊·哈拉比博士和达娜·拉斯科普夫博士的合作下，我们组装了一个 临床研究人员和生物统计学家组成的团队在前瞻性研究中快速验证这一多重生物标志物 学习。这种基于RNA的CTC检测方法显示出识别耐药前列腺癌的潜力 这是对患者的初步研究，因此有望在分析和临床验证方面取得成功。