Validation of prognostic and pathway signatures in lethal prostate cancer

致命性前列腺癌的预后和通路特征的验证

• 批准号: 8338858
• 负责人: PHILLIP G FEBBO
• 金额: $ 52.51万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-26 至 2013-08-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8338858
• 关键词: Aggressive behavior; Androgens; Automobile Driving; Behavior; Biological Assay; Biological Markers; Biological Process; Biology; Cancer Etiology; Cancer and Leukemia Group B; Chromosomal translocation; Clinical; Clinical Trials; Collaborations; Combined Modality Therapy; Communities; Computer Simulation; DNA; Data; Data Set; Databases; Diagnosis; Disease; Enrollment; Ensure; Event; Family member; Freezing; Future; Genetic; Gleason Grade for Prostate Cancer; Grant; Hereditary Disease; Internet; Laboratories; Lead; Local Therapy; Localized Malignant Neoplasm; Malignant Neoplasms; Malignant neoplasm of prostate; Medical Oncologist; MicroRNAs; Modality; Molecular; Neoadjuvant Therapy; Nomograms; Operative Surgical Procedures; Outcome; Paraffin Embedding; Pathology; Pathway interactions; Patients; Phase III Clinical Trials; Phenotype; Principal Investigator; Process; Prostatectomy; Publications; RNA; RNA analysis; Radiation; Randomized; Recurrence; Reliance; Reproducibility; Research Design; Research Personnel; Resources; Risk; Risk Assessment; Role; Sampling; Standardization; System; Testing; Time; Tissues; United States; Update; Urologist; Validation; base; biobank; cancer therapy; cohort; deprivation; docetaxel; follow-up; high risk; high risk men; improved; insight; interdisciplinary approach; interest; meetings; men; mortality; prognostic; programs; prospective; statistical center; tumor; wiki

DESCRIPTION (provided by applicant): Prostate cancer remains the most commonly diagnosed malignancy in men in the United States and a leading cause of cancer related mortality. Nomograms and multi-variable tables identify men at high risk for recurrence following definitive local therapy but provide little insight as to the specific biology driving aggressive disease. Recent findings have highlighted the role for genetic translocations in lethal disease and molecular-based prognostic and pathway signatures have the potential to guide multi-modality therapy and improve the potential for cure. Our proposal will validate established RNA-, DNA-, and microRNA prognostic and pathway signatures in both a retrospective and prospective cohort of men with high-risk prostate cancer. We will first comprehensively assay a retrospective cohort of 200 men who have had prostatectomy, have frozen and paraffin embedded tissue available, and have mature clinical follow up. This cohort will be processed through a centralized system including the CALGB pathology coordinating office, assayed in laboratories with established expertise in comprehensive RNA-, DNA-, and microRNA analysis, and results will be analyzed in the CALGB Statistical Center. This cohort will provide the initial validation of prognostic and predictive signatures and determine how these signatures relate to ETS-family member and RAF translocations. The most informative signatures will be re-derived by the statistical center, re-applied to the retrospective dataset to confirm reproducibility of the computational models, and then applied to a samples from CALGB 90203, a prospective, randomized phase III trial that will randomize 750 men between immediate surgery or neoadjuvant docetaxel and androgen deprivation therapy followed by surgery. In addition, computational investigators will perform integrative analysis of RNA-, DNA-, and microRNA data so as to distinguish "driver" pathways responsible for the lethal phenotype from "bystander" pathways that are correlated with aggressiveness but not causative. Finally, promising, validated signatures will be adapted to paraffin-embedded tissue so as to develop clinically deployable bioassays. Our proposal leverages two outstanding cohorts, the scientific and computational expertise in five independent laboratories, the established capabilities of industrial partners, and the statistical rigor of the CALGB to validate prognostic and pathway signatures in high-risk prostate cancer. All data will be shared through GEO and other emerging databases so as to ensure that along with the insight resulting from our own analysis, our data will be an outstanding resource for the larger investigative community interested in the validation of prognostic signatures in high-risk prostate cancer.

描述（由申请人提供）：前列腺癌仍然是美国男性中最常诊断出的恶性肿瘤，也是癌症相关死亡的主要原因。列线图和多变量表可识别出在明确的局部治疗后具有高复发风险的男性，但对驱动侵袭性疾病的特定生物学提供的见解很少。最近的研究结果强调了基因易位在致命疾病中的作用，基于分子的预后和通路特征有可能指导多模式治疗并提高治愈的潜力。我们的提案将在回顾性和前瞻性的高危前列腺癌男性队列中验证已建立的 RNA、DNA 和 microRNA 预后和通路特征。我们将首先全面分析 200 名接受过前列腺切除术、拥有冷冻和石蜡包埋组织并具有成熟临床随访的男性的回顾性队列。该队列将通过包括 CALGB 病理学协调办公室在内的集中系统进行处理，在具有综合 RNA、DNA 和 microRNA 分析专业知识的实验室进行分析，结果将在 CALGB 统计中心进行分析。该队列将提供预后和预测特征的初步验证，并确定这些特征与 ETS 家族成员和 RAF 易位的关系。统计中心将重新得出信息最丰富的签名，重新应用于回顾性数据集以确认计算模型的可重复性，然后应用于 CALGB 90203 的样本，CALGB 90203 是一项前瞻性随机 III 期试验，将随机化 750 名受试者。立即手术或新辅助多西紫杉醇和雄激素剥夺治疗后再手术的男性。此外，计算研究人员将对 RNA、DNA 和 microRNA 数据进行综合分析，以便区分导致致死表型的“驱动”途径和与攻击性相关但与致病性无关的“旁观者”途径。最后，有希望的、经过验证的特征将适用于石蜡包埋的组织，以便开发临床上可部署的生物测定法。我们的提案利用两个杰出的队列、五个独立实验室的科学和计算专业知识、工业合作伙伴的既定能力以及 CALGB 的统计严谨性来验证高风险前列腺癌的预后和途径特征。所有数据将通过 GEO 和其他新兴数据库共享，以确保与我们自己分析得出的见解一起，我们的数据将成为对验证高风险前列腺预后特征感兴趣的更大研究社区的杰出资源癌症。