Emory, Harvard & Univ. of Washington Prostate Cancer Biomarker Center

 描述（由申请人提供）：我们假设，针对侵袭性前列腺癌的早期检测将使治疗致死性疾病的生存获益，并减少对惰性疾病过度治疗的危害。为了实现这一目标，我们通过严格的SOP在旨在避免偏倚的队列中组装生物标本样本集。我们向Discovery Labs、行业和联盟提供这些样本和研究设计指导。DMCC、霍普金斯BRL、行业合作伙伴、UTHSC-SA和我们的CVC之间的团队努力促进了FDA批准前列腺健康指数（phi -来自我们CVC第一个周期的数据）和尿PCA 3（来自当前周期的数据）。在两个资助周期中，我们的CVC招募了4，821名受试者。我们帮助Chinnaiyan BDL将TMPRSS 2：Erg融合（T2：Erg）的发现推向可操作的临床应用，完成了3个目标，并于4日取得进展：首先，我们将T2：Erg的尿液检测与尿液PCA 3相结合，以提高Gleason评分> 7的癌症检测的特异性，在多中心队列中验证了该算法，并显示了通过该算法在65岁以下男性中降低医疗保健成本的潜力。其次，我们描述了独立于PSA筛查的尿T2：Erg、PCA 3和phi的社区分布，并发现了这些参数的种族差异，为IV期筛查试验铺平了道路（国防部正在审查的单独提案）。第三，我们将前列腺切除术组织Erg表达与尿T2：Erg进行比较，指导适当的尿T2：Erg临界点范围以反映组织状态。第四，我们从两个全国范围的回顾性观察等待队列（PHS和HPFS）获得活检，将受试者招募到PASS试验中，并组装适合于评估多重RNA的生物样本集，以区分侵袭性疾病和惰性疾病。认识到T2：Erg作为癌症侵袭性分类器的局限性，我们开始了24个基因的临床翻译， 用于区分侵袭性和惰性前列腺癌的多重RNA组;显示了该测定在活检组织和尿液中的可行性，并确定了在临床级平台上评估该特征的行业合作伙伴。我们将扩大我们的验证研究，包括成像，以评估癌症的严重程度，基于FACBC，PET放射性示踪剂正在临床开发。我们正在扩大我们的CVC的广度，从以前仅限于学术医疗中心（AMC），现在包括一个城市贫困护理医院，退伍军人管理局医疗中心和一个郊区社区医院（除了我们的主机AMC），以便我们计划招募1050名非洲裔美国人，大大多样化EDRN生物标本资源。我们现在提出以下目的：1）验证尿PCA 3、T2：Erg和血清phi的组合作为原发性侵袭性前列腺癌的预测和用于主动监测; 2）验证活检样品和DRE后尿液中侵袭性前列腺癌的多重RNA特征; 3）验证FACBC作为检测高风险、局限性前列腺癌中的隐匿性转移性疾病的成像; 4）与EDRN BDL、CVC和BRL合作，推进前列腺癌生物标志物的开发。

 DESCRIPTION (provided by applicant): We hypothesize that early detection, targeting aggressive prostate cancer, will enable survival benefits of treatment for lethal disease, and reduce harms of over-treatment for indolent disease. Toward this goal, we assemble biospecimen sample sets via rigorous SOP's in cohorts designed to avoid bias. We provide these specimens and guidance regarding study design to Discovery Labs, industry and consortia. Team efforts between the DMCC, the Hopkins BRL, industry partners, UTHSC-SA and our CVC facilitated FDA approval of the Prostate Health Index (phi - with data from our CVC's first cycle), and urinary PCA3 (with data from the current cycle). In two funding cycles, our CVC enrolled 4,821 subjects. We helped advance the TMPRSS2:Erg fusion (T2:Erg) discovery by the Chinnaiyan BDL toward actionable clinical use, completing 3 Aims with progress on the 4th: First, we combined urinary detection of T2:Erg with urinary PCA3 to improve specificity of detecting cancers with Gleason score > 7, validated this algorithm in a multi-center cohort, and showed the potential to reduce health care cost via this algorithm in men less than 65 years old. Second, we characterized community-based distribution of urinary T2:Erg, PCA3, and phi independent of PSA screening, and found race- based differences in these parameters, paving the way for a phase IV screening trial (separate proposal under review by DOD). Third, we compared prostatectomy tissue Erg expression to urinary T2:Erg, guiding the range of appropriate urinary T2:Erg cut-points to reflect tissue status. Fourth, we procured biopsies from two nation- wide, retrospective watchful waiting cohorts (PHS and HPFS), enrolled subjects onto the PASS Trial, and assembled a biospecimen set suitable for evaluating multiplex RNA's to discern aggressive from indolent disease. Recognizing limitations of T2:Erg as a classifier of cancer aggressiveness, we initiated clinical translation of a 24-gene, multiplex RNA panel for discerning aggressive from indolent prostate cancer; showed the feasibility of this assay in biopsy tissue and urine, and identified an industry partner to evaluat this signature on a clinical grade platform. We will expand our validation studies to include imaging to assess cancer severity based on FACBC, a PET radiotracer undergoing clinical development. We are expanding the breadth of our CVC from previously being limited to academic medical centers (AMC's), to now including an urban indigent care hospital, a Veterans Administration Medical Center, and a suburban community hospital (in addition to our host AMC) so that we project enrolling 1050 African-American men, substantially diversifying the EDRN biospecimen resource. We now propose the following Aims: 1) To validate the combination of urine PCA3, T2:Erg and serum phi as predictive of aggressive prostate cancer de novo and for active surveillance; 2) To validate a multiplex RNA signature of aggressive prostate cancer in biopsy samples and post-DRE urine; 3) To validate FACBC as imaging to detect occult metastatic disease in high-risk, localized prostate cancer; 4) To collaborate with EDRN BDL's, CVC's and BRL's to advance prostate cancer biomarker development.