Project 3: Towards Understanding Prostate Cancer Heterogeneity

项目3：总结 虽然高危局限性前列腺癌(PCa)通常通过包括根治性治疗在内的多种治疗方法治愈 前列腺摘除、放射治疗和雄激素剥夺治疗与去势的发展 耐药前列腺癌(CRPC)转移后进展是致命的。来自几个组织的研究表明 分析的未经处理的局部PCA和CRPC，但这些研究代表来自方便的 早期治疗时代的样本或快速尸检。缺乏针对前列腺癌的分子研究 在目前的治疗或临床试验中取得进展。近日，一支由多家机构组成的“梦之队”成立了 对来自中国的转移性肿瘤活检组织(和生殖系DNA)进行完整外显子组(WES)和RNA测序 500名CRPC患者(CRPC500研究)在参加涉及苯扎鲁胺、阿比特龙、 和PARP抑制剂(Olaparib)。我们最近发表了第一批150个案例(Robinson等人，《细胞2015》)和 已有500多名男性入选，预计将在未来3年内进行临床随访。我们现在有了 非同寻常的机会检查原始的未经治疗的诊断材料从前列腺 并将其与转移样本进行比较，以探索与 进展为CRPC和治疗反应。 我们的团队开发了下一代测序(NGS)分析，使福尔马林固定石蜡的讯问成为可能 嵌入(FFPE)示例。Exact-1是CLEP(CLIA)批准的WES检测和相关分析 用于700多个转移和原发样本/正常配对的管道(威尔·康奈尔医学)。 作为对这一检测的补充，还有一种针对10-20 ng进行优化的针对PCA的特定版本的肿瘤肿瘤研究小组 FFPE DNA和RNA(大学密歇根州)。这些方法允许对未经治疗的原发肿瘤进行分析 CRPC500例。我们的首要目标是确定早期突变/其他分子 改变告知疾病进展和对AR或PARP指导治疗的反应。

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.!