Cell free nucleic acid-based biomarkers in advanced prostate cancer

晚期前列腺癌中基于无细胞核酸的生物标志物

• 批准号: 9751257
• 负责人: Manish Kohli
• 金额: $ 10.48万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2019-12-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9751257
• 关键词: Ablation; Algorithms; Androgens; Biological; Biological Assay; Biological Markers; Biological Models; Blood; Body Fluids; Cancer Cell Growth; Cancer Patient; Castration; Cell Count; Cells; Clinical; DNA; DNA sequencing; Development; Disease Progression; FDA approved; Failure; Genes; Genomics; Growth; High-Throughput Nucleotide Sequencing; Hormonal; Hormones; Human; In Vitro; Individual; Knowledge; Laboratories; Malignant neoplasm of prostate; Medicine; Metastatic Prostate Cancer; MicroRNAs; Molecular; Molecular Abnormality; Mutation; Neoplasm Circulating Cells; Nucleic Acids; Nude Mice; Outcome; Pain; Patient-Focused Outcomes; Patients; Performance; Plasma; Plasma Cells; Prediction of Response to Therapy; Predictive Factor; Prognostic Factor; Prognostic Marker; Progression-Free Survivals; Quantitative Reverse Transcriptase PCR; RNA; Reporting; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Technology; Testing; Time; Treatment Protocols; Tumor Burden; Tumor-Derived; Unfavorable Clinical Outcome; Validation; androgen deprivation therapy; base; cancer recurrence; castration resistant prostate cancer; cell free DNA; chemotherapy; circulating microRNA; cohort; design; digital; docetaxel; effective therapy; in vivo; liquid biopsy; microRNA biomarkers; outcome forecast; patient response; pre-clinical; precision medicine; predicting response; prediction algorithm; predictive marker; predictive modeling; predictive test; predictive tools; prognostic; prognostic assays; prognostic performance; prognostic tool; prospective; prostate cancer cell; prostate cancer model; prostate cancer progression; research clinical testing; response; transcriptome sequencing; treatment response; tumor; tumor growth; tumor progression; tumor xenograft; whole genome

PROJECT SUMMARY Metastatic hormone-sensitive prostate cancer is treated with androgen deprivation therapy and after progression to the castration-resistant prostate cancer stage, with additional forms of hormonal ablation and/or with chemotherapy. These treatments slow tumor progression by a certain period and decrease the pain and suffering from disease progression. However, there is no clinical feature or molecular test that can reliably predict these treatment responses or clinical outcomes in advanced prostate cancer. A predictive feature or biomarker which is defined as a factor determining which patients will do well with a specific type of treatment. This is distinct from molecular prognostic biomarkers which provide information about clinical outcome regardless of therapy used. Knowledge of predictive factors that identify cohorts of patients destined for response (versus failure) of these therapies is critically needed to develop precision medicine strategies. Recently, the assessment of tumor-derived cell free nucleic acids in body fluids has shown promise in being able to capture tumor genomic and genetic abnormalities in cancer patients. This approach is often referred to as “liquid biopsy”. We believe that cell free nucleic acids can be used as biomarkers to reliably predict treatment response and clinical outcomes, and will therefore be informative in designing an appropriate treatment regimen. We have previously examined plasma cell free nucleic acids for miRNA abundance and somatic DNA changes in patients with advanced prostate cancer. We observed a significant association of high plasma miRNAs (miR-375 and miR- 1290) with poor overall survival. We also observed that tumor-derived genomic/genetic alterations in plasma cell free DNAs were associated with tumor burden and reflected patients' responses to stage-specific treatments. Aim 1 of this study is to identify and validate key circulating miRNA-based predictive and prognostic biomarkers in four well annotated prostate cancer cohorts. Aim 2 is to establish circulating cell free DNA-based predictive and prognostic biomarkers in four well annotated prostate cancer cohorts. Aim 3 is to functionally characterize the potential of the key candidate miRNAs in promoting growth and resistance of prostate cancer cells to androgen deprivation therapy or chemotherapy in vitro and in vivo. The proposed studies are highly significant and timely, as the circulating cell free nucleic acid-based biomarkers will not only help clinicians in selecting the most effective treatment options, but also provide important clues regarding mechanisms that underlie prostate cancer progression and recurrence.

项目摘要 转移性辣根敏感的前列腺癌通过雄激素剥夺治疗和进展后治疗 到cast割的前列腺癌阶段，具有其他形式的激素消融和/或 化学疗法。这些治疗方法会慢慢肿瘤进展一定时期，并减轻疼痛和 患有疾病进展。但是，没有临床特征或分子测试可以可靠地预测 这些治疗反应或晚期前列腺癌的临床结果。预测功能或生物标志物 这被定义为确定哪些患者在特定类型的治疗方面做得很好的因素。这是 与分子预后生物标志物不同，这些生物标志物提供有关临床结果的信息 使用的治疗。了解预测因素的知识，这些因素鉴定了注定应对反应的患者的同龄人（与 这些疗法的失败是至关重要的，以制定精确的医学策略。最近，评估 体液中肿瘤衍生的无细胞核酸的核酸已显示出有望捕获肿瘤基因组的有望 癌症患者的遗传异常。这种方法通常称为“液体活检”。我们相信 无细胞的核酸可以用作生物标志物，以可靠地预测治疗反应和临床 结果，因此将在设计适当的治疗方案时提供信息。我们以前有 检查了缺乏血浆细胞的核酸的miRNA丰度和体细胞DNA的变化 晚期前列腺癌。我们观察到高血浆miRNA的显着关联（miR-375和mir- 1290）总生存率差。我们还观察到血浆细胞中肿瘤衍生的基因组/遗传改变 游离DNA与肿瘤灼伤有关，并反映了患者对特异性治疗的反应。 这项研究的目标1是识别和验证基于miRNA的预测和预后生物标志物的关键循环 在四个注释良好的前列腺癌队列中。 AIM 2是建立基于无DNA的循环细胞的预测 以及四个注释良好的前列腺癌队列中的预后生物标志物。目标3是在功能上表征 关键候选miRNA在促进前列腺癌细胞的生长和抵抗力方面的潜力 雄激素剥夺疗法或体内化学疗法。拟议的研究非常重要 及时，由于基于无核酸的循环细胞生物标志物不仅可以帮助临床医生选择 最有效的治疗选择，但也提供有关前列腺基础机制的重要线索 癌症的进展和复发。