Michigan Prostate SPORE

自1995年成立以来，密歇根大学（U-M）前列腺孢子已经开发出巨大的 智力和物质资源的U-M社区，以减少发病率和死亡率的前列腺 癌（PCa）。在这次更新申请中，密歇根大学与Karmanos癌症研究所（KCI）联手提出了一项 “密歇根州前列腺孢子”利用我们机构各自的优势领域。KCI具有非重叠 患者人群作为U-M，其中包括服务不足的人群。密歇根州前列腺孢子支持 一个互动的基础和临床研究小组在一个转化研究计划，导致了重大 发现在诊断，预防和治疗前列腺癌。成功翻译的发现在 最近的资助期包括：1）ETS基因融合体（这是由这个孢子计划发现） 已被确立为早期检测PCa的尿液检测（JAMA Oncology 2017 3：1085）， 已经用拟肽抑制剂治疗靶向（Cancer Cell 2017 31：844）。2)我们的SPORE计划 在确定转移性去势抵抗性前列腺的临床可行性方面发挥了重要作用， 癌症（mCRPC）（Cell 2015，162：454），这导致发现超过20-25%的mCRPC具有 DNA修复基因的缺陷作为TO-PARP研究的一部分，我们发现，DNA修复的mCRPC患者 缺陷优先响应PARP抑制剂（NEJM 2015，373：1697）。3)确定BET布罗莫结构域 抑制剂可通过阻断致癌转录因子活性而用于治疗晚期PCa （Nature 2014，510：278）。4)几种PCA相关的长非编码RNA，包括PCAT 1、Schlap 1（Nature Genetics 2013 45：1392）和ARlnc 1（Nature Genetics 2018，50：814）的基因组中。这些 与华盛顿大学的横向合作帮助了从工作台到床边的应用， Dana Farber、Memorial Sloan-Kettering和Weill-Cornell前列腺孢子以及EDRN和垂直 与SWOG和生物技术公司合作。该应用程序由四个项目组成：项目1： 靶向CDK 12双等位基因缺失的mCRPC患者;项目2：整合基于MiPS的新型Next- 用于早期检测不利风险PCa的一代测序尿液检测;项目3：探索 雄激素受体消融作为mCRPC的治疗方法;项目4：靶向自噬， mCRPC的治疗这些项目得到了强有力的、持续的机构承诺的补充， 资金和空间，成功的职业发展和发展研究计划，以及三个 核心：管理、生物统计/生物信息学和生物标本/病理学。密歇根前列腺 SPORE继续对其转化研究项目进行严格的科学审查， 基础和临床研究人员，利用PCa领域内外科学家的专业知识， 并利用灵活性为有前途的新研究方法提供资金。我们多学科小组的互动 调查人员的调查清楚地表明，密歇根州的前列腺孢子大于其各个部分的总和。

Since inception in 1995, the University of Michigan (U-M) Prostate SPORE has endeavored to tap the vast intellectual and physical resources of the U-M community to decrease the morbidity and mortality of prostate cancer (PCa). In this renewal application, U-M joins forces with Karmanos Cancer Institute (KCI) to propose a “Michigan Prostate SPORE” leveraging our institutions' respective areas of strength. KCI has a non-overlapping patient population as U-M, which includes an underserved population. The Michigan Prostate SPORE supports an interactive group of basic and clinical investigators in a translational research program that has led to major discoveries in the diagnosis, prevention, and treatment of PCa. Successful translation of discoveries in the most recent grant period include: 1) The ETS gene fusions (which were discovered by this SPORE program) have been established as a urine test for the early detection of PCa (JAMA Oncology 2017 3:1085) and have been therapeutically targeted with peptidomimetic inhibitors (Cancer Cell 2017 31:844). 2) Our SPORE program played a significant role in defining the clinically actionable landscape of metastatic castration-resistant prostate cancer (mCRPC) (Cell 2015, 162:454) which led to the discovery that upwards of 20-25% of mCRPC harbor defects in DNA repair genes. As part of the TO-PARP study, we showed that mCRPC patients with DNA repair defects preferentially respond to PARP inhibitors (NEJM 2015, 373:1697). 3) Established that BET bromodomain inhibitors may be useful in the treatment of advanced PCa by blocking oncogenic transcription factor activity (Nature 2014, 510:278). 4) Several PCa-associated long non-coding RNAs, including PCAT1, Schlap1 (Nature Genetics 2013 45:1392), and ARlnc1 (Nature Genetics 2018, 50:814) were discovered and characterized. These bench-to-bedside applications were aided by horizontal collaborations with the University of Washington, Dana Farber, Memorial Sloan-Kettering, and Weill-Cornell Prostate SPOREs as well as the EDRN and vertical collaborations with SWOG and biotech companies. This application consists of four projects: Project 1: Targeting mCRPC Patients with Biallelic Loss of CDK12; Project 2: Integrating a Novel MiPS-Based Next- Generation Sequencing Urine Assay for the Early Detection of Unfavorable Risk PCa; Project 3: Exploring Ablation of the Androgen Receptor as a Therapeutic Approach for mCRPC; Project 4: Targeting Autophagy in the Treatment of mCRPC. These projects are complemented by strong, ongoing institutional commitments of money and space, successful Career Development and Developmental Research Programs, and three cores: Administration, Biostatistics/Bioinformatics, and Biospecimen/Pathology. The Michigan Prostate SPORE continues to place premiums on rigorous scientific review of its translational research programs, pairing of basic and clinical investigators, drawing on expertise of scientists from within and from outside the PCa field, and utilizing flexibility to fund promising new research approaches. The interaction of our multidisciplinary group of investigators clearly makes the Michigan Prostate SPORE greater than the sum of its individual parts.