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发现将使致命疾病的治疗带来生存益处，并减少对惰性疾病过度治疗的危害。为了实现这一目标，我们通过严格的标准操作规程在队列中组装生物样品集，以避免偏见。我们向探索实验室、行业和财团提供这些样本和研究设计指南。DMCC、Hopkins 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对前列腺健康指数(Phi-使用我们CVC第一周期的数据)和尿PCA3(使用当前周期的数据)的批准。在两个资助周期中，我们的CVC招收了4821名受试者。我们帮助Chinnaiyan BDL将TMPRSS2：ERG融合(T2：ERG)的发现推向了可操作的临床应用，完成了3个目标，并在4日取得了进展：首先，我们将尿T2：ERG检测与尿PCA3相结合，以提高Gleason Score&gt；7检测癌症的特异性，并在多中心队列中验证了该算法，并显示出通过该算法在65岁以下男性中降低医疗费用的潜力。其次，我们描述了独立于PSA筛查的基于社区的尿T2：ERG、PCA3和PHI的分布，并发现这些参数基于种族的差异，为第四阶段筛查试验(国防部正在审查的单独提案)铺平了道路。第三，我们比较了前列腺切除组织ERG的表达和尿液T2：ERG的表达，指导了合适的尿液T2：ERG切点的范围以反映组织状态。第四，我们从两个全国性的、有追溯性观察的等待队列(PHS和HPFS)获得活检组织，将受试者纳入PASS试验，并组装了一套适合评估多重RNA的生物标本集，以区分侵袭性和惰性疾病。认识到T2：ERG作为癌症侵袭性分类器的局限性，我们启动了一个24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小组；在活检组织和尿液中展示了这种分析的可行性，并确定了在临床分级平台上评估这一特征的行业合作伙伴。我们将扩大我们的验证研究，以包括基于FACBC的成像来评估癌症严重程度，FACBC是一种正在临床开发的PET放射性示踪剂。我们正在扩大我们CVC的范围，从以前局限于学术医疗中心(AMC)，到现在包括一家城市贫困护理医院、一家退伍军人管理医疗中心和一家郊区社区医院(除了我们的东道主AMC)，以便我们计划招收1050名非裔美国人，大大多样化EDRN生物医学资源。我们现在提出以下目标：1)验证尿PCA3、T2：ERG和血清PHI联合预测侵袭性前列腺癌新生和积极监测的价值；2)验证活检样本和DRE后尿液中侵袭性前列腺癌的多重RNA信号；3)验证FACBC在高危、局限性前列腺癌中检测隐匿性转移疾病的影像价值；4)与EDRN BDL‘s、CVC’s和BRL‘s合作，推进前列腺癌生物标记物的开发。

 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.