Early detection of ovarian cancer by serum marker and targeted ultrasound imaging

摘要 我们建议测试我们的靶向超声成像探头在早期检测中的有效性和特异性。 通过经阴道超声成像（TVUS）对卵巢癌（OVCA）进行分期。然后我们测试预测有效性 这些探针在纵向研究中使用蛋鸡-唯一广泛使用的动物模型， 自发性OVCA。卵巢癌是一种致命的妇科恶性肿瘤。有效的早期检测测试 可以显著降低OVCA的高死亡率和与探查手术相关的发病率。 血清CA-125水平、传统TVUS及其联合均未能提高OVCA的早期检出率。 CA-125是非特异性的，卵巢中没有与血清CA-125升高相对应的成像靶点 程度.需要一种新的方法。有效的靶向成像策略需要适当的靶点， 合适的成像模态/平台。我们的显像剂，第一次，将检测卵巢肿瘤， 肿瘤相关新生血管生成（TAN）微血管。超声目前用于评估 泌尿生殖道肿块，并引入早期OVCA检测的分子显像剂， 医生使用现有的TVUS设备。我们开发了TVUS成像探针， 激素受体（FSHR）表达卵巢TAN微血管和葡萄糖调节蛋白78（GRP 78）- 表达卵巢肿瘤上皮。我们在产蛋鸡中测试了这些探针。我们的初步数据支持 这些探针与血清标志物联合使用TVUS检测早期OVCA的有效性和特异性 提供原理证明。因此，在目标1中，我们提出开发新的靶向超声成像 包括FSHR和GRP 78靶向成像探针的试剂。目标2将建立目标成像 检测早期OVCA的强度。目标3将测试这些探针检测早期阶段的能力 建立鸡模型的假阳性率。由于难以确定病人在 早期OVCA和访问他们的组织，我们将使用蛋鸡来实现我们的研究目标。 由于该团队包括临床医生，我们的目的是开发这些探针供人类使用，这可能是 立即翻译到诊所。

ABSTRACT We propose to test the validity and specificity of our targeted ultrasound imaging probes in detecting early stage ovarian cancer (OVCA) by transvaginal ultrasound imaging (TVUS). We then test the predictive validity of these probes in a longitudinal study using the laying hen – the only widely available animal model of spontaneous OVCA. OVCA is a fatal gynecological malignancy of women. An effective early detection test could reduce high mortality rate due to OVCA and morbidity associated with exploratory surgeries significantly. Serum levels of CA-125, traditional TVUS and their combination failed to improve early detection of OVCA. CA-125 is non-specific and there is no imaging target in the ovary corresponding to elevated serum CA-125 levels. A fresh approach is needed. An efficient targeted imaging strategy requires appropriate targets and suitable imaging modalities/platforms. Our imaging agents, for the first time, will detect the ovarian tumor and tumor associated neo-angiogenic (TAN) microvessels. Ultrasound is currently used for evaluation of genitourinary masses, and introduction of molecular imaging agents for early OVCA detection would enable physicians to use existing TVUS equipment. We developed TVUS imaging probes targeting follicle stimulating hormone receptor (FSHR) expressing ovarian TAN microvessels and glucose regulatory protein 78 (GRP78)- expressing ovarian tumor epithelium. We tested these probes in laying hens. Our preliminary data supports the validity and specificity of these probes for detecting early OVCA using TVUS in association with serum markers providing proof-of-principle. Thus, in Aim 1 we are proposing to develop novel targeted ultrasound imaging agents including FSHR- and GRP78-targeted imaging probes. Aim 2 will establish the targeted imaging intensities for the detection of early stage OVCA. Aim 3 will test the ability of these probes to detect early stage OVCA and establish the false positive rate in the hen model. Because of the difficulty of identifying patients at early stage OVCA and accessing their tissues, we will use the laying hen to accomplish our research goals. Since the team includes clinicians, our intent is to develop these probes for human use, which could be immediately translated into the clinic.