Biomarker Developmental Laboratory

项目摘要/摘要 癌症筛查可以及早发现癌症，降低死亡率。然而，高假阳性率和低假阳性率 肺癌(LC)和卵巢癌(OC)筛查的敏感性导致不必要的手术和漏诊 癌症。我们的首要目标是开发循环生化标记物，以减少假阳性 提高CT对LC的诊断率，提高OC筛查的阳性预测值 CA125和经阴道超声(TVUS)。我们假设LC和OC患者有不同的抗体 良性疾病受试者的免疫反应可用于检测癌症和排除 非癌症的。我们将采用系统的方法处理三种类型的抗体：自身抗体、抗微生物抗体 抗体和抗异常糖蛋白抗体。我们的建议基于我们在以下方面的丰富经验 癌症生物标记物的发现和免疫蛋白质组学技术。我们之前对自身抗体的研究结果 生物标志物已在盲探阶段2多中心验证研究中得到确认。我们的结果显示 自身抗体生物标记物对癌症具有高度特异性；尽管，需要多种自身抗体 有足够的预测价值。微生物在癌症与良性疾病中的作用日益受到关注 发展，这可以通过不同的总感染率和/或不同的免疫反应来观察 来自各种微生物的个体抗原。蛋白糖基化异常是LC和OC的标志，我们 将利用我们独特的能力以高通量展示糖基化蛋白质。成功者 实施我们的研究需要在蛋白质组水平上评估抗体的高通量方法。 在EDRN的支持下，我们开发了一套创新的免疫蛋白质组学技术，即高 密度核酸可编程蛋白质阵列(HD-NAPPA)、反向捕获蛋白质阵列(CCPA)和 多溶液蛋白质阵列(MISPA)，与最大的全长人类和微生物基因相结合 收集(DNASU质粒库)，使我们能够研究针对完整的人类蛋白质组的抗体， 微生物蛋白质组和人类O-糖蛋白质组在癌症中的抗体生物标记物特征。我们的 之前的成功，Videssa®Breast，这是一种CLIA认证的乳腺癌血液测试，临床上用于 乳房X光检查包括一组自身抗体标志物和血清蛋白标志物。与Videssa®一样， 我们还将使用中尺度诊断(MSD)多阵列平台来评估报告的血清蛋白 用于补充我们的LC和OC抗体标记物。我们将在以下方面与专家合作 波士顿大学范德比尔特大学医学中心的LC和OC筛查 中心和德国癌症研究中心，谁也将提供高质量的 我们目标人群的样本。我们将通过筛选蛋白质阵列来执行第一阶段(探针)发现 与癌症和对照血清的癌症或对照特异性抗体。LC和LC的候选生物标记物 OC将进行第二阶段-使用ELISA或MISPA检测进行验证。

Project Summary/Abstract Cancer screening can detect cancer early and reduce mortality. However, high false positive rates and low sensitivities of lung (LC) and ovarian cancer (OC) screening result in unnecessary surgeries and missed cancers. Our overarching goal is to develop circulating biochemical biomarkers that reduce the false positive rate of the CT scan for LC and increase the positive predictive value of OC screening in combination with CA125 and trans-vaginal ultrasound (TVUS). We hypothesize that LC and OC patients have different antibody immune responses from subjects with benign diseases that can be explored for detecting cancer and excluding non-cancer. We will take a systems approach working with 3 types of antibodies: autoantibodies, anti-microbial antibodies and anti-aberrant glycoprotein antibodies. Our proposal builds on our extensive experience with cancer biomarker discovery and immunoproteomics technology. Our previous results on autoantibody biomarkers have been confirmed in blinded PRoBE phase 2 multicenter validation studies. Our results showed that autoantibody biomarkers are highly specific for cancer; although, multiple autoantibodies are needed for adequate predictive value. There is increased attention to the role microbes play in cancer vs. benign disease development, which can be observed by different overall infection rates and / or immune responses to different individual antigens from various microbes. Aberrant protein glycosylation is a hallmark of LC and OC, and we will exploit our unique capability to display glycosylated proteins in high throughput. The successful implementation of our study entails high throughput methods for assessing antibodies at the proteome level. With EDRN support, we have developed a set of innovative immunoproteomics technologies, namely high- density nucleic acid programmable protein array (HD-NAPPA), contra-capture protein array (CCPA) and multiple in solution protein array (MISPA), that, combined with the largest full-length human and microbial gene collection (DNASU plasmid repository), enable us to study antibodies against the full human proteome, microbial proteomes and the human O-glycoproteome for antibody biomarker signatures in cancer. Our previous success, Videssa® Breast, which is a CLIA-certified blood test for breast cancer used clinically with mammography, includes a panel of both autoantibody markers and serum protein markers. As with Videssa®, we will also use the Meso Scale Diagnostics (MSD) MultiArray platform to assess reported serum protein markers for their utility to complement our antibody markers for LC and OC. We will collaborate with experts on LC and OC screening at Vanderbilt University Medical Center, Boston University, MD Anderson Cancer Center, and German Cancer Research Center, who will also provide access to high quality well-characterized samples from our target populations. We will perform Phase I (PRoBE) discovery by screening protein arrays with cancer and control sera for cancer- or control-specific antibodies. Candidate biomarkers for both LC and OC will be Phase 2-validated using ELISA or MISPA assays.