Role of Macrophages in Resistance to Anti-VEGF Drugs in Ovarian Cancer

项目总结(见说明)： 孢子计划1的目标是开发有效的策略，以早期检测卵巢癌。 患病风险处于中等水平的女性。鉴于卵巢癌在绝经后人群中的流行 女性，诊断策略必须中等敏感(&gt；75%)，但高度特异(&gt；99.6%)才能实现 阳性预测值为10%，即每发现一例卵巢癌就进行10次开腹手术。其中一个 早期发现这种肿瘤最有希望的方法是使用血清标记物的升高。 如CA125，以促进经阴道超声(TVS)的表现。电视异常患者 或CA125升高足够快的患者接受探查手术。在上一次授权期内，我们有 对这一策略进行了评估，发现其积极预测值为30%。如果要采取分两个阶段的战略 对于早期检测，初始阶段必须是最灵敏的。任何单一的标记都不可能足够 可能需要敏感和多个标记物来检测卵巢癌的全部谱系。简单 添加多个标记物可能会提高敏感性，但通常会降低特异性，从而导致特定的 与卵巢癌的流行有关的疾病的问题。我们已经确定了一个由四个生物标记物组成的小组 (CA125、HE4、CEA和sVCAM-1)检测87%的早期疾病，特异性为98%。在这个项目中， 我们的目标是1：评估一种算法对早期诊断的特异性和阳性预测值。 根据每年测量的一组血清生物标志物检测卵巢癌。多种生物标志物 承诺提高对早期和临床前疾病的敏感性，前提是保持特异性， 允许在一小部分参与者中播放电视。我们将检验这一假设 多个生物标志物的价值将促使不超过2%的女性转介电视，并实现 阳性预测值&gt；10%。目的2：建立多项血清生物标志物的“服务点”检测方法 使用芯片实验室传感器系统，该系统对手指棒上的血液进行处理。筛查可能是 简化，如果结果立即可用，不需要静脉穿刺术。我们将测试 假设用芯片上的实验室纳米系统测量四种生物标志物的水平将 与标准实验室化验结果相关联。目的3：早期鉴定一组血清自身抗体 卵巢癌的检测。小体积的卵巢癌可能不会释放足够的抗原 检测到，但可能会引起抗体反应。我们将检验一种假设，即检测自身抗体 突变和野生型蛋白将提高对不会提高抗原水平的卵巢癌的检测。

PROJECT SUMMARY (See instructions): The goal of SPORE Project 1 is to develop effective strategies for earty detection of ovanan cancer in women at average risk for the disease. Given the prevalence of ovanan cancer among postmenopausal women, a diagnostic strategy must be moderately sensitive (>75%), but highly specific (>99.6%) to achieve a positive predictive value of 10%, i.e., 10 laparotomies for each case of ovarian cancer detected. One of the most promising approaches to early detection of this neoplasm is to use rising values of a serum marker such as CA 125 to prompt the performance of transvaginal sonography (TVS). Patients with abnormal TVS or a sufficiently rapid rise in CA 125 undergo exploratory surgery. During the last grant period, we have evaluated this strategy and found a positive predictive value of 30%. If one is to pursue a two-stage strategy for earty detection, the initial stage must be optimally sensitive. No single marker is likely to be adequately sensitive and multiple markers may be required to detect the full spectrum of ovarian cancers. Simple addition of multiple markers may increase sensitivity, but generally decreases specificity, posing a particular problem in a disease with the prevalence of ovarian cancer. We have identified a panel of four biomarkers (CA125, HE4, CEA and sVCAM-1) that detect 87% of early stage disease at 98% specificity. In this project, our aims are Aim 1: To evaluate the specificity and positive predictive value of an algorithm for early detection of ovarian cancer based on a panel of serum biomarkers measured annually. Multiple biomarkers promise to increase sensitivity for earty stage and preclinical disease, provided that specificity is maintained, permitting performance of TVS in a small fraction of participants. We will test the hypothesis that rising values of multiple biomarkers will prompt the referral of no more than 2% of women for TVS and achieve a positive predictive value >10%. Aim 2: To develop a "point of service" test for multiple serum biomarkers using a lab-on-a-chip sensor system that is performed on blood from a finger-stick. Screening could be simplified if results were immediately available and venipuncture was not required. We will test the hypothesis that measurement of the levels of the four biomarkers with a lab-on-a-chip.nanosystem will correlate with standard laboratory assays. Aim 3: To identify a panel of serum autoantibodies for eariy detection of ovarian cancer. Small volumes of ovanan cancer may not release sufficient antigen to be detected, but could evoke an antibody response. We will test the hypothesis that detection of autoantibodies to mutant and wild-type proteins will improve detection of ovarian cancers that do not elevate antigen levels.