Project 3: Towards Understanding Prostate Cancer Heterogeneity

项目3：概要 尽管高危局限性前列腺癌（PCa）通常通过多模式治疗（包括根治性前列腺癌）治愈， 睾丸切除术，放射治疗[RT]和雄激素剥夺治疗[ADT]，去势的发展 转移进展后的耐药前列腺癌（CRPC）是致命的。几个研究小组的研究表明， 然而，这些研究代表了来自方便的静态快照， 早期治疗时期的样本或快速尸检。缺乏针对PCa的分子研究 在目前的治疗或临床试验期间进展。近日，一个多机构的“梦之队”组建 对转移性肿瘤活检（和生殖系DNA）进行全外显子组（WES）和RNA测序， 在入组涉及Enzalutamide、阿比特龙、 和PARP抑制剂（奥拉帕尼）。我们最近发表了前150例（罗宾逊等人，Cell 2015） 超过500名男子参加了研究，预计将在未来3年内进行临床随访。我们现在有 这是一个非常好的机会，可以检查来自前列腺的原始未经处理的诊断材料。 CRPC 500例患者，并将其与转移性样本进行比较，以探索与 进展为CRPC和治疗应答。 我们的团队开发了下一代测序（NGS）检测方法，可以对福尔马林固定的石蜡进行询问。 包埋（FFPE）样品。EXaCT-1是CLEP（CLIA）批准的WES检测试剂盒，具有相关分析 在超过700个转移性和原发性样本/正常对上使用的管道（Weill Cornell Medicine）。 补充该测定的是针对10- 20 ng优化的Oncomine Cancer Panel的PCA特异性版本 FFPE DNA和RNA（密歇根大学）。这些方法允许分析未经治疗的原发性肿瘤， CRPC 500例患者。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定向治疗的反应。

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.!