Cancer Detection & Diagnosis Research-2022-Comprehensive genomic profiling of aggressive hormone sensitive prostate cancer

癌症检测

• 批准号: 10890557
• 负责人: CHRISTOPHER J SWEENEY
• 金额: $ 36.78万
• 依托单位: UNIVERSITY OF ADELAIDE
• 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 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10890557
• 关键词: Ablation; Address; Aftercare; American College of Radiology Imaging Network; Androgens; BRCA2 gene; Biochemical; Biological Markers; Cancer Detection; Castrate sensitive prostate cancer; 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; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Gene Mutation; Genes; Genome; Genomics; Hormonal; Literature; Localized Disease; Malignant neoplasm of prostate; Medical Research; Metastatic Prostate Cancer; 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; Research; Resistance; Sampling; Screening Result; Source; Systemic Therapy; TP53 gene; Therapeutic; Time; Tissues; Training; Tumor Suppressor Genes; Widespread Disease; Work; Zoledronic Acid; abiraterone; androgen deprivation therapy; arm; biomarker identification; biomarker validation; cancer diagnosis; castration resistant prostate cancer; chemotherapy; clinical prognostic; docetaxel; drug efficacy; efficacy trial; exome; exome sequencing; gene repair; genomic profiles; hormone therapy; improved; insight; loss of function; men; participant enrollment; phase III trial; pre-clinical; predictive marker; predictive modeling; prevent; prognostic; prognostic model; prognostic of survival; prognostication; prospective; response; side effect; treatment response; 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，导致了174,650例新病例中的大多数 在美国前列腺癌​​，转移性和治疗性疾病仍有大约31,620例死亡。 为了使样品的基因分析能够识别我们已收集的预后和预测性生物标志物 来自988名独特患者的肿瘤样本参加了两项完整的第三阶段试验： E3805CHAARTED：化学型疗法与雄激素消融试验的广泛疾病试验 前列腺癌。 Sweeney等人，N Eng J Med 2015，373（8）：737-46。 MRCPR08 Stampede：添加多西他赛，唑来膦酸或两者兼有一线长期激素 前列腺癌的治疗（Stampede）：生存来自自适应，多学院，多阶段，平台 随机对照试验，James，N。D.等人，等等2016，387（10024）：1163-1177。 这提供了一个非常独特的机会来研究基因概况并识别与良好相关的生物标志物 与对荷尔蒙治疗的反应不良，用于转移性龙杆菌敏感的前列腺癌（MHSPC）。这个5- R01年的应用重点是评估与抑制肿瘤基因改变有关的基因组谱 导致p53，PTEN和RB1的功能丧失。临床前和临床数据支持以下假设 这些肿瘤补充剂基因中突变的存在与对ADT的反应不佳有关。 这两个试验的样本提供了首次的机会，可以预期评估一个还是 这些突变中有更多的突变可以在开始治疗之前识别患者 对ADT的回应。反过 从早期加入多西他赛。这可能允许精确的患者选择和不备用的患者 受益于多西他的早期化学治疗的副作用。 我们将首先对肿瘤和种系DNA的整个外显子组测序以及全面的RNA 使用ChaArted试验中的Affymetrix平台进行剖面，以有效，全面询问 基因组。然后，我们将开发临床结构组模型，以确定是否更准确的预后 通过外显子组的变量组合可以实现从早期多西他赛获得的收益的预测 突变和/或基因表达谱（GEP）和/或临床因素。锁定模型后，我们将 然后尝试验证踩踏样品中的预后和预测模型。 这也值得突出显示，整个外显子组测序和GEP的这种广泛方法也将允许 我们根据新兴的临床前和临床数据进行询问和其他探索其他假设 与DNA损伤修复基因有关的那些（例如BRCA2）。这项工作也可能导致确定 靶向预防ADT抗性并改善MHSPC男性存活的途径。

项目成果

Accumulation of copy number alterations and clinical progression across advanced prostate cancer.

• DOI: 10.1186/s13073-022-01080-4
• 发表时间: 2022-09-05
• 期刊: Genome medicine
• 影响因子: 12.3

Testosterone suppression plus enzalutamide versus testosterone suppression plus standard antiandrogen therapy for metastatic hormone-sensitive prostate cancer (ENZAMET): an international, open-label, randomised, phase 3 trial.

睾酮抑制加恩杂鲁胺与睾酮抑制加标准抗雄激素疗法治疗转移性激素敏感型前列腺癌 (ENZAMET)：一项国际、开放标签、随机、3 期试验。

• DOI: 10.1016/s1470-2045(23)00063-3
• 发表时间: 2023
• 期刊: The Lancet. Oncology
• 作者: Sweeney,ChristopherJ;Martin,AndrewJ;Stockler,MartinR;Begbie,Stephen;Cheung,Leanna;Chi,KimN;Chowdhury,Simon;Frydenberg,Mark;Horvath,LisaG;Joshua,AnthonyM;Lawrence,NicolaJ;Marx,Gavin;McCaffrey,John;McDermott,Ray;McJannett,
• 通讯作者: McJannett,