Cell free nucleic acid-based biomarkers in advanced prostate cancer

项目摘要 转移性前列腺癌敏感性前列腺癌接受雄激素剥夺治疗，进展后 至去势抵抗性前列腺癌阶段，与其他形式的激素消融和/或与 化疗这些治疗将肿瘤进展减缓一定时间，并减少疼痛， 患有疾病进展。然而，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。预测特征或生物标志物 其被定义为确定哪些患者将在特定类型的治疗中表现良好的因素。这是 与提供关于临床结果的信息的分子预后生物标志物不同， 使用的治疗。了解可识别预期缓解患者队列的预测因素（与 这些疗法的失败）是迫切需要开发精确的医学策略。最近，评估 在体液中的肿瘤衍生的无细胞核酸已经显示出能够捕获肿瘤基因组的希望， 和基因异常的癌症患者。这种方法通常被称为“液体活检”。我们认为 无细胞核酸可用作生物标志物，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。我们先前已经 检查了血浆细胞游离核酸的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miRNAs（miR-375和miR-275）与高血浆miRNAs（miR-275和miR-275）之间的显著相关性。 #21290;，总体生存率低。我们还观察到浆细胞中肿瘤源性基因组/遗传改变， 游离DNA与肿瘤负荷相关，反映了患者对分期特异性治疗的反应。 本研究的目的1是鉴定和验证关键的基于循环miRNA的预测和预后生物标志物 在四个很好注释的前列腺癌队列中。目的二是建立基于循环游离细胞DNA的预测模型， 和预后生物标志物。目标3是功能特性 关键候选miRNAs在促进前列腺癌细胞生长和抵抗前列腺癌细胞增殖中的潜力， 雄激素剥夺疗法或化学疗法在体外和体内。拟议的研究非常重要 并且及时，因为基于循环无细胞核酸的生物标志物不仅将帮助临床医生选择合适的生物标志物， 最有效的治疗选择，而且还提供了有关前列腺疾病机制的重要线索， 癌症进展和复发。

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.