Project 3: Towards Understanding Prostate Cancer Heterogeneity

项目 3：了解前列腺癌异质性

基本信息

批准号：
10227731
负责人：
MARK A. RUBIN
金额：
$ 34.65万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
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：
2017-08-30 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10227731
关键词：
Address Autopsy Biological Assay Biopsy CLIA certified Cancer Patient Cells Clinical Clinical Trials Combined Modality Therapy Complement DNA DNA Repair DNA Repair Gene Data Data Analyses Development Diagnosis Diagnostic Disease Progression Dreams Early treatment Enrollment Formalin Frequencies Gene Mutation Genomics Goals Heterogeneity Immunohistochemistry Lesion Logistics Malignant Neoplasms Malignant neoplasm of prostate Mediator of activation protein Medicine Memorial Sloan-Kettering Cancer Center Metastatic to Michigan Molecular Molecular Profiling Mutation Neoplasm Metastasis Oncogenic Output PARP inhibition PTEN gene Paraffin Embedding Pathology Patients Performance Primary Neoplasm Prostate Prostate Cancer therapy Prostatectomy Publications Publishing RB1 gene RNA RNA Splicing Radiation therapy Radical Prostatectomy Resistance Running Sampling Specimen Structure of base of prostate TP53 gene Testing The Cancer Genome Atlas Time Variant abiraterone analysis pipeline androgen deprivation therapy base brca gene cBioPortal cancer heterogeneity castration resistant prostate cancer clinical decision-making cohort data pipeline exome exome sequencing experience follow-up gene repair high risk high risk population indexing individual patient inhibitor/antagonist insight men next generation sequencing oncotype predictive marker prognostic signature prostate cancer progression response transcriptome sequencing transcriptomics treatment response treatment trial tumor

项目摘要

PROJECT 3: SUMMARY Although high risk localized prostate cancer (PCa) is often cured by multimodal therapy including radical prostatectomy, radiation therapy [RT] and androgen deprivation therapy [ADT], the development of castration resistant prostate cancer (CRPC) after metastatic progression is lethal. Studies from several groups have profiled untreated localized PCa and CRPC, however these studies represent static snapshots from convenient samples or rapid autopsies from earlier treatment eras. Lacking are molecular studies addressing PCa progression during current treatments or clinical trials. Recently, a multi-institutional “Dream Team” was formed to perform whole exome (WES) and RNA sequencing on metastatic tumor biopsies (and germline DNA) from 500 CRPC patients (the “CRPC500” study) prior to enrollment on trials involving enzalutamide, abiraterone, and a PARP inhibitor (olaparib). We recently published the first 150 cases (Robinson et al., Cell 2015) and over 500 men have been enrolled with clinical follow-up expected through the next 3 years. We now have the extraordinary opportunity to examine the original untreated diagnostic material from the prostates of the CRPC500 patients and compare it to the metastatic samples to explore key critical questions relevant to progression to CRPC and treatment response. Our team developed next generation sequencing (NGS) assays enabling interrogation of formalin-fixed paraffin embedded (FFPE) samples. EXaCT-1 is a CLEP (CLIA) approved WES assay with an associated analysis pipeline used on over 700 metastatic and primary sample/normal pairs (Weill Cornell Medicine). Complementing this assay is a PCa-specific version of the Oncomine Cancer Panel optimized for 10-20ng FFPE DNA and RNA (Univ. Michigan). These approaches allow analysis of untreated primary tumors from CRPC500 patients. Our overarching goal is to determine the extent to which early mutations/other molecular alterations inform on disease progression and response to AR or PARP directed therapy.!

项目 3：总结尽管高风险局限性前列腺癌 (PCa) 通常可以通过包括根治性治疗在内的多模式治疗来治愈前列腺切除术、放射治疗 [RT] 和雄激素剥夺疗法 [ADT]、去势的发展多个小组的研究表明，转移进展后的耐药性前列腺癌（CRPC）是致命的。分析了未经处理的局部 PCa 和 CRPC，但是这些研究代表了方便的静态快照缺乏针对早期治疗时代的样本或快速尸检。最近，在当前的治疗或临床试验中，一个多机构的“梦之队”成立了。对转移性肿瘤活检（和种系 DNA）进行全外显子组 (WES) 和 RNA 测序在纳入涉及恩杂鲁胺、阿比特龙、我们最近发表了前 150 个病例（Robinson 等人，Cell 2015）和超过 500 名男性已入组并预计在未来 3 年内进行临床随访。检查来自前列腺的原始未经处理的诊断材料的绝佳机会 CRPC500 名患者并将其与转移样本进行比较，以探讨与 CRPC 进展和治疗反应。我们的团队开发了新一代测序 (NGS) 检测方法，能够对福尔马林固定石蜡进行询问嵌入式 (FFPE) 样本是 CLEP (CLIA) 批准的 WES 检测方法，并具有相关分析功能。用于 700 多个转移性和原发性样本/正常对的管道（Weill Cornell Medicine）。 Oncomine Cancer Panel 的 PCa 特异性版本针对 10-20ng 进行了补充，以补充该检测 FFPE DNA 和 RNA（密歇根大学）。这些方法可以分析未经治疗的原发性肿瘤。我们的首要目标是确定 CRPC500 名患者的早期突变/其他分子的程度。改变可告知疾病进展以及对 AR 或 PARP 定向治疗的反应。！