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，但 174,650 例新病例中的大部分都得到了早期识别 在美国前列腺癌​​中，仍有约 31,620 人死于转移性和治疗耐药性疾病。 为了对样本进行基因分析以识别预后和预测生物标志物，我们收集了 来自参加两项已完成的 3 期试验的 988 名独特患者的肿瘤样本：  E3805 CHAARTED：针对广泛性疾病的化学激素疗法与雄激素消融试验 前列腺癌。 Sweeney 等人，N Eng J Med 2015，373(8)：737-46。  MRC PR08 STAMPEDE：在一线长期激素中添加多西紫杉醇、唑来膦酸或两者 前列腺癌治疗 (STAMPEDE)：适应性、多臂、多阶段平台的生存结果 随机对照试验，James, N. D., et al Lancet 2016, 387(10024):1163-1177。 这提供了一个非常独特的机会来研究基因谱并识别与良好相关的生物标志物。 与转移性激素敏感前列腺癌 (mHSPC) 激素治疗反应不佳相比。这个5- R01年申请重点评估与抑癌基因改变相关的基因组图谱 导致 p53、PTEN 和 RB1 功能丧失。临床前和临床数据支持以下假设： 这些抑癌基因突变的存在与 ADT 反应不佳有关。这 这两项试验的样本首次提供了前瞻性评估是否有一个或一个的机会。 更多的这些突变可以在开始治疗之前识别出注定病情不佳的患者 对 ADT 的反应。反过来，这些突变中的一种或多种的存在可能会识别出受益的患者 早期添加多西紫杉醇。这可以允许准确的患者选择并避免那些没有选择的患者 早期使用多西紫杉醇可缓解这种化疗药物的副作用。 我们将首先对肿瘤和种系 DNA 以及综合 RNA 进行全外显子组测序 使用来自 CHAARTED 试验的 Affymetrix 平台进行概要分析，以高效、全面地询问 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 可以通过外显子组变量的组合来预测早期多西紫杉醇的益处 突变和/或基因表达谱（GEP）和/或临床因素。锁定模型后，我们将 然后尝试验证 STAMPEDE 样本中的预后和预测模型。 还值得强调的是，这种采用全外显子组测序和 GEP 的广泛方法也将允许 我们根据新出现的临床前和临床数据来询问和探索其他假设，例如 与 DNA 损伤修复基因（例如 BRCA2）相关的基因。这项工作还可能导致识别 旨在预防 ADT 耐药性出现并提高 mHSPC 男性生存率的途径。