Comprehensive genomic profiling of aggressive hormone sensitive prostate cancer

侵袭性激素敏感前列腺癌的全面基因组分析

• 批准号: 10155449
• 负责人: CHRISTOPHER J SWEENEY
• 金额: $ 57.79万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10155449
• 关键词: Ablation; Address; Aftercare; American College of Radiology Imaging Network; Androgens; BRCA2 gene; Biochemical; Biological; Biological Markers; Cessation of life; Characteristics; Clinical; Clinical Data; Clinical Trials; Companions; DNA; DNA Repair; DNA Sequence Alteration; Data; Development; Disease; Disease Resistance; Drug Evaluation; Early identification; Eastern Cooperative Oncology Group; Enrollment; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Gene Mutation; Genes; Genome; Genomics; Hormones; Lead; Literature; Localized Disease; Malignant neoplasm of prostate; Medical Research; Metastatic Prostate Cancer; Metastatic to; Modeling; Mutation; Naturopathic Doctor; Outcome; PTEN gene; Pathway interactions; Patient Selection; Patient-Focused Outcomes; Patients; Prognosis; Prognostic Marker; Prostate; Publishing; RB1 gene; RNA; Randomized Controlled Trials; Recurrence; Relapse; Resistance; Sampling; Screening Result; Source; Systemic Therapy; TP53 gene; Time; Tissues; Training; Tumor Suppressor Genes; Widespread Disease; Work; Zoledronic Acid; abiraterone; androgen deprivation therapy; base; biomarker validation; cancer survival; castration resistant prostate cancer; chemotherapy; docetaxel; drug efficacy; efficacy trial; exome; exome sequencing; gene repair; genomic profiles; hormone therapy; improved; insight; loss of function; men; phase III trial; pre-clinical; predictive marker; predictive modeling; prevent; prognostic; prognostic model; prognostic of survival; prospective; response; side effect; tumor

Despite a high rate of screening resulting in early identification of most of the 174,650 new cases of prostate cancer in the USA, there are still about 31,620 deaths for metastatic and treatment resistant disease. To enable gene profiling of the samples to identify prognostic and predictive biomarkers we have collected tumor samples from 988 unique patients enrolled on two completed phase 3 trials:  E3805 CHAARTED: ChemoHormonal Therapy versus Androgen Ablation Trial for Extensive Disease in Prostate cancer. Sweeney et al, N Eng J Med 2015, 373(8):737-46.  MRC PR08 STAMPEDE: Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial, James, N. D., et al Lancet 2016, 387(10024):1163-1177. This offers a very unique opportunity to study gene profiles and identify biomarkers associated with a good versus poor response to hormonal therapy for metastatic hormone sensitive prostate cancer (mHSPC). This 5- year R01 application focuses on assessing genomic profiles related to alterations of tumor suppressor genes leading to loss of function of p53, PTEN and RB1. Preclinical and clinical data supports the hypothesis that the presence of mutations in these tumor suppressors genes are associated with a poor response to ADT. The samples from the two trials provide the opportunity for the first time to prospectively assess whether one or more of these mutations can identify patients prior to starting treatment who are destined to have a poor response to ADT. In turn, the presence of one or more of these mutations may identify patients who benefit from adding in docetaxel early. This may allow accurate patient selection and spare patients who did not benefit from early docetaxel the side effects of this chemotherapeutic. We will first perform whole exome sequencing of the tumor and germline DNA and comprehensive RNA profile using the Affymetrix platform from the CHAARTED trial to efficiently and comprehensively interrogate the genome. We will then develop clinicogenomic models to determine whether more accurate prognostication and prediction of benefit from early docetaxel can be achieved with a combination of variables from the exome mutation and/or gene expression profiles (GEP) and/or clinical factors. Having locked down models, we will then attempt to validate the prognostic and predictive models in the STAMPEDE samples. It is also worth highlighting, this broad approach with whole exome sequencing and GEP will also allow us to interrogate and other explore other hypotheses based on emerging preclinical and clinical data such as those pertaining to DNA Damage Repair genes (e.g. BRCA2). This work may also lead to identification of pathways to target to prevent emergence of resistance to ADT and improve the survival of men with mHSPC.

尽管筛查率很高，导致早期发现了174,650例新病例中的大多数 前列腺癌在美国，仍有大约31,620人死于转移性和耐药疾病。 为了能够对样本进行基因图谱分析，以确定预后和预测性生物标志物，我们收集了 来自988名独特患者的肿瘤样本参加了两项已完成的3期试验： E3805特点：化疗激素治疗与雄激素消融治疗广泛性疾病的对比试验 前列腺癌。[2]Sweeney等，N Eng J Med 2015,373(8)：737-46. MRCPR08踩踏：在一线长期激素的基础上添加多西紫杉醇和/或唑来膦酸 前列腺癌的治疗(踩踏)：适应性、多臂、多阶段、平台的生存结果 《随机对照试验》，《柳叶刀》，第387期(10024)：1163-1177。 这提供了一个非常独特的机会来研究基因图谱和识别与良好的 而转移性激素敏感型前列腺癌(MHSPC)对激素治疗的反应较差。本5- R01年的应用重点是评估与肿瘤抑制基因变化相关的基因组图谱 导致P53、PTEN和RB1功能丧失。临床前和临床数据支持这一假设 这些肿瘤抑制基因突变的存在与ADT的不良反应有关。这个 这两项试验的样本首次提供了前瞻性评估一个或多个 更多的这些突变可以在开始治疗之前识别出注定有不良预后的患者 对ADT的反应。反过来，这些突变中的一个或多个的存在可能识别出受益的患者 从早期加入多西紫杉醇开始。这可能会允许准确的患者选择，并免除那些没有 受益于早期多西他赛这种化疗药物的副作用。 我们将首先对肿瘤和生殖系DNA和综合RNA进行完整的外显子组测序 使用CHAARTED试验的Affymetrix平台高效、全面地询问个人资料 基因组。然后我们将开发临床基因组模型来确定是否有更准确的预测 预测早期多西紫杉醇的益处可以通过外显子组的变量组合来实现。 突变和/或基因表达谱(GEP)和/或临床因素。锁定模特后，我们将 然后尝试在踩踏事件样本中验证预测模型和预测模型。 同样值得强调的是，这种带有整个外显子组测序和GEP的广泛方法也将允许 美国将基于新出现的临床前和临床数据询问和其他探索其他假说，如 与DNA损伤修复基因有关的基因(例如BRCA2)。这项工作还可能导致识别 靶向预防对ADT耐药的出现和提高男性mHSPC患者存活率的途径。