Predictive Cancer Diagnostics and Therapy Response

描述（由申请人提供）：在任何明显的生理症状出现之前，在分子失调的最早阶段诊断癌症的能力将允许立即进行治疗干预，从而提高存活率。在我们的原始申请R 01 CA 135650“乳腺癌进展和治疗反应的多参数监测”中，我们确定了低糖基化粘蛋白1肿瘤抗原（uMUC 1）在癌前阶段发生改变，并且我们可以在乳腺癌小鼠模型中使用非侵入性MR成像检测这种癌前转化。这与来自乳腺癌患者的人活检样品中uMUC 1表达的分析相一致，所述分析显示与来自无癌症史的女性的组织相比，在邻近癌症病变的正常组织中抗原显著上调（但在病理学报告中被鉴定为“正常”）。此外，我们观察到下调uMUC 1抗原在化疗研究中的转基因人乳腺肿瘤模型，使用非侵入性MRI。这些数据表明，uMUC 1在乳腺癌发生过程中很早就发生了改变，可以作为癌症检测和治疗的预测性生物标志物。在本更新申请中，我们建议扩展这些研究以评估uMUC 1的广泛预测性癌症诊断和治疗反应，因为它在超过50%的人类癌症中过度表达和糖基化不足。这将通过首先在非癌性、邻近正常和恶性临床组织样品中建立uMUC 1与其他腺癌（胰腺癌、结肠直肠癌和卵巢癌）的相关性来完成。接下来，我们将使用表达人uMUC 1的胰腺癌、结直肠癌和卵巢癌的动物模型，并通过定量跟踪uMUC 1肿瘤抗原的相对丰度，测试我们是否可以使用我们的成像方法预测和监测恶性转化。与我们的原始申请一样，对于MR成像和uMUC 1靶向，我们将利用肿瘤特异性造影剂（MN-EPPT），其由与肽（EPPT）结合的氧化铁纳米颗粒（MN，可通过磁共振成像检测）组成，对uMUC 1具有特异性。最后，我们将通过在已建立的动物模型中进行治疗研究来评估uMUC 1作为化疗反应的预测生物标志物的全球相关性。我们期望在化疗过程中通过基于MN-EPPT积累的MRI监测肿瘤大小变化之前观察uMUC 1可用性的变化。这将与肿瘤分期以及化疗成功相关，如通过相对存活率和肿瘤细胞凋亡的诱导所定义的。

DESCRIPTION (provided by applicant): The ability to diagnose cancer at the earliest stages of molecular dysregulation before any overt physiologic symptoms have developed would permit immediate therapeutic intervention resulting in higher survival rates. In our original application R01 CA135650 "Multi-parameter monitoring of breast cancer progression and therapeutic response" we established that underglycosylated mucin1 tumor antigen (uMUC1) is altered in the premalignant stage and that we can detect this premalignant transformation using noninvasive MR imaging in a mouse model of breast cancer. This coincided with analysis of uMUC1 expression in human biopsy samples from breast cancer patients that showed a marked upregulation of the antigen in the normal tissues adjacent to cancer lesions (but identified as "Normal" on pathology reports) compared to tissues from women with no cancer history. Furthermore, we observed down regulation of the uMUC1 antigen in chemotherapy studies in a transgenic human breast tumor model using noninvasive MRI. These data indicate that uMUC1 is altered very early in the process of breast carcinogenesis and could serve as a predictive biomarker for cancer detection and therapy. In this renewal application we propose to extend these studies to evaluate uMUC1 for a wide- ranging predictive cancer diagnostics and therapy response considering that it is over expressed and underglycosylated on over 50% of human cancers. This will be done by first establishing relevance of uMUC1 to other adenocarcinomas (pancreatic, colorectal, and ovarian) in non-cancerous, adjacent normal, and malignant clinical tissue samples. Next, we will use animal models of pancreatic, colorectal, and ovarian cancers expressing human uMUC1 and test whether we can predict and monitor malignant transformation using our imaging approach by quantitatively tracking the relative abundance of the uMUC1 tumor antigen. As in our original application, for MR imaging and uMUC1 targeting we will utilize tumor-specific contrast agent (MN-EPPT) that consists of iron oxide nanoparticles (MN, detectable by magnetic resonance imaging) conjugated to peptides (EPPT), specific for uMUC1. Finally, we will evaluate global relevance of uMUC1 as a predictive biomarker of chemotherapy response by performing therapy studies in established animal models. We expect to observe changes in uMUC1 availability prior to changes in tumor size as monitored by MRI based on MN-EPPT accumulation during the course of chemotherapy. This will be correlated with tumor stage, as well as with chemotherapeutic success, as defined by relative survival and induction of tumor cell apoptosis.