Cell free nucleic acid-based biomarkers in advanced prostate cancer

项目总结 转移性激素敏感型前列腺癌的雄激素剥夺治疗及其进展 抗去势前列腺癌阶段，附加形式的激素消融和/或 化疗。这些治疗方法在一定时间内延缓肿瘤的进展，减轻疼痛和 遭受疾病进展的折磨。然而，没有临床特征或分子检测可以可靠地预测 这些治疗反应或晚期前列腺癌的临床结果。预测性特征或生物标志物 它被定义为决定哪些患者在特定类型的治疗中表现良好的因素。这是 与分子预后生物标志物不同，分子预后生物标志物提供关于临床结果的信息，无论 使用了治疗方法。了解预测因素，以确定接受治疗的患者队列(与 这些疗法的失败)对于发展精确的医学策略是至关重要的。最近，这项评估 体液中肿瘤细胞游离核酸的研究显示，能够捕获肿瘤基因组是有希望的 以及癌症患者的基因异常。这种方法通常被称为“液体活检”。我们相信 无细胞核酸可以作为生物标志物可靠地预测治疗反应和临床 结果，并因此将在设计适当的治疗方案方面提供信息。我们之前已经 检测慢性粒细胞白血病患者血浆游离核酸的miRNA丰度和体细胞DNA变化 晚期前列腺癌。我们观察到高血浆miRNAs(miR-375和miR- 1290)，总体存活率较低。我们还观察到，肿瘤衍生的基因组/遗传改变在浆细胞中 游离DNA与肿瘤负担相关，并反映了患者对特定阶段治疗的反应。 这项研究的目标1是识别和验证循环中基于miRNA的关键预测和预后生物标志物 在四个有良好注解的前列腺癌队列中。目标2是建立基于循环中无细胞DNA的预测 以及四个有良好注解的前列腺癌队列中的预后生物标记物。目标3是从功能上描述 关键候选miRNAs在促进前列腺癌细胞生长和对其耐药性方面的潜力 体内和体外雄激素剥夺治疗或化疗。拟议的研究具有非常重要的意义 而及时，作为循环中的游离核酸生物标志物，不仅将有助于临床医生选择 最有效的治疗方案，但也提供了关于前列腺癌潜在机制的重要线索 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.