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

基本信息

批准号：
10240337
负责人：
Manish Kohli
金额：
$ 59.42万
依托单位：
H. LEE MOFFITT CANCER CTR & RES INST
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10240337
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 Prognosis 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 advanced prostate cancer 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 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

项目摘要

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.

项目概要转移性激素敏感性前列腺癌采用雄激素剥夺疗法和进展后治疗到去势抵抗性前列腺癌阶段，采用其他形式的激素消融和/或这些治疗可在一定时间内减缓肿瘤进展并减轻疼痛和疼痛。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是预测特征或生物标志物。它被定义为决定哪些患者能够接受特定类型治疗的良好因素。与分子预后生物标志物不同，分子预后生物标志物提供有关临床结果的信息，无论所使用的治疗的知识，用于识别预期有反应的患者群体（与其他患者相比）。最近，对这些疗法的评估对于制定精准医学策略至关重要。体液中肿瘤来源的无细胞核酸的研究已显示出能够捕获肿瘤基因组的希望我们认为这种方法通常被称为“液体活检”。无细胞核酸可以用作生物标志物来可靠地预测治疗反应和临床结果，因此将为我们之前设计适当的治疗方案提供信息。检查血浆细胞游离核酸的 miRNA 丰度和体细胞 DNA 变化我们观察到高血浆 miRNA（miR-375 和 miR-）存在显着关联。 1290），我们还观察到浆细胞中肿瘤衍生的基因组/遗传改变。游离 DNA 与肿瘤负荷相关，反映了患者对特定阶段治疗的反应。本研究的目标 1 是识别和验证基于 miRNA 的关键循环预测和预后生物标志物目标 2 是建立基于循环细胞游离 DNA 的预测。目标 3 是对四个注释良好的前列腺癌队列中的预后生物标志物进行功能表征。关键候选 miRNA 在促进前列腺癌细胞生长和抵抗力方面的潜力体外和体内雄激素剥夺疗法或化疗非常重要。而且及时，因为循环无细胞核酸生物标志物不仅有助于选择最有效的治疗方案，而且还提供有关前列腺机制的重要线索癌症进展和复发。