Identification of Ovarian Cancer Plasma Biomarkers

卵巢癌血浆生物标志物的鉴定

• 批准号: 8759302
• 负责人: DAVID W. SPEICHER
• 金额: $ 44.07万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8759302
• 关键词: Antibodies; Benign; Biological; Biological Assay; Biological Markers; Blood; Blood Tests; CA-125 Antigen; Cancer Biology; Cancer Patient; Cause of Death; Cell Line; Clear Cell; Clinical; Clinical Management; Complement; Diagnosis; Disease; Early Diagnosis; Enzyme-Linked Immunosorbent Assay; Epithelial ovarian cancer; Evaluation; Exhibits; FDA approved; Future; Goals; Grant; Health; Hematopoietic Neoplasms; Human; Image; Immunohistochemistry; Immunoprecipitation; Individual; Label; Laboratories; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Mass Spectrum Analysis; Methods; Molecular Weight; Mucinous; Mucinous Neoplasm; Mus; Normal tissue morphology; Outcome; Ovarian Mucinous Adenocarcinoma; Ovarian Mucinous Tumor; Pathology; Patients; Peptide antibodies; Performance; Plasma; Preclinical Testing; Predictive Value; Progress Reports; Proteins; Proteome; Proteomics; Sampling; Sensitivity and Specificity; Serous; Serum; Site; Stable Isotope Labeling; Staging; System; Testing; Time; Tissues; Tumor Subtype; Tumor Tissue; United States; Validation; WFDC2 gene; Woman; Work; Xenograft procedure; base; cohort; cost; expectation; improved; in vivo; insight; mouse model; multiple reaction monitoring; novel; ovarian neoplasm; pre-clinical; public health relevance; stable isotope; tumor

DESCRIPTION (provided by applicant): There is an urgent need for new blood biomarkers for epithelial ovarian cancer (EOC), which is the most lethal gynecological cancer in the United States. CA125 is the most commonly used FDA approved biomarker for EOC, but it is not approved for early diagnosis due to inadequate sensitivity and specificity. Furthermore, although CA125 is commonly used to assist in clinical management of the disease after diagnosis, it cannot be used for the substantial portion of EOC patients where CA125 is not substantially elevated at time of diagnosis, which includes the clear cell and mucinous subtypes. Our long-term goal is to identify novel EOC blood-based and tumor tissue biomarkers and conduct laboratory-scale validation to determine which biomarkers can improve early diagnosis and/or clinical management of this disease. Our overall working hypothesis is that the most specific EOC blood biomarkers will be proteins shed by the ovarian tumor into the blood and that are at very low abundance levels in the blood of cancer-free individuals. During the past grant year, we achieved all goals of the original proposal. Specifically, we identified 29 low-abundance, novel biomarkers using a novel in-depth proteome analysis method to identify human proteins in serum or plasma of xenografted mice containing human tumors. These proteins were then shown to be elevated in blood from EOC patients compared with non-cancer controls using a label-free multiplexed multiple reaction monitoring (MRM) mass spectrometry (MS) assay. We have now narrowed this list to 12 high priority biomarkers using biological and functional criteria Our specific goal for the next grant period is to conduct laboratory-scale validation of these 12 biomarkers in several larger patient cohorts to identify the best biomarkers for early diagnosis of EOC and for improved clinical management of this disease. We will also conduct preliminary evaluations of the capacities of these biomarkers to distinguish among major EOC subtypes, as these are genetically different diseases. To determine whether some biomarkers could complement CA125, we will conduct a focused evaluation of secretomes of clear cell and mucinous ovarian tumors. We will also separately evaluate the predictive value of our biomarkers in the subset of patient plasma samples that exhibit low CA125 levels in our new larger patient cohorts. The two aims that will be pursued over a 5- year period are: 1) Develop tissue and high-throughput preclinical plasma assays for our 12 novel EOC biomarkers, and 2) Validate sensitivity and specificity of our 12 novel EOC biomarker levels in plasma or serum from multiple independent patient cohorts. The biomarkers will be quantified in patient and control plasma or serum using a novel ImmunoMRM method that multiplexes pull-down of targeted intact proteins by commercially-available antibodies using stable isotope-labeled intact proteins as internal standards. It is expected that the subset of our 12 biomarkers that are shown to be useful for early diagnosis and/or clinical management of EOC will advance to larger-scale multi-center, preclinical testing in CLIA certified laboratories in the future.

描述（由申请人提供）：上皮性卵巢癌（EOC）是美国最致命的妇科癌症，目前迫切需要新的血液生物标志物。CA125是FDA批准的EOC最常用的生物标志物，但由于灵敏度和特异性不足，未被批准用于早期诊断。此外，尽管CA125通常用于诊断后的临床治疗，但它不能用于大部分诊断时CA125水平不明显升高的EOC患者，包括透明细胞和粘液亚型。我们的长期目标是确定新的EOC血液和肿瘤组织生物标志物，并进行实验室规模的验证，以确定哪些生物标志物可以改善这种疾病的早期诊断和/或临床管理。我们的总体工作假设是，最具体的EOC血液生物标志物将是卵巢肿瘤释放到血液中的蛋白质，而这些蛋白质在无癌症个体的血液中含量非常低。在过去的奖助金年度，我们达到了原计划的所有目标。具体来说，我们使用一种新的深入蛋白质组学分析方法鉴定了29种低丰度的新型生物标志物，以鉴定含有人类肿瘤的异种移植小鼠血清或血浆中的人类蛋白质。然后，使用无标记多路多反应监测（MRM）质谱（MS）分析显示，与非癌症对照组相比，EOC患者血液中的这些蛋白质升高。我们现在已经根据生物学和功能标准将这个列表缩小到12个高优先级的生物标志物。我们下一个拨款期的具体目标是在几个更大的患者队列中对这12个生物标志物进行实验室规模的验证，以确定早期诊断的最佳生物标志物