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。在我们最初的应用R01 CA135650“乳腺癌进展和治疗反应的多参数监测”中，我们确立了低糖基化粘蛋白1肿瘤抗原(UMUC1)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。这与对乳腺癌患者活检样本中uMUC1表达的分析不谋而合，该分析显示，与没有癌症病史的女性组织相比，癌病变附近的正常组织(但在病理报告中被确认为“正常”)中uMUC1的抗原显著上调。此外，我们使用非侵入性MRI在转基因人类乳腺肿瘤模型中观察到uMUC1抗原在化疗研究中的下调。这些数据表明，uMUC1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生物标志物。在这次更新应用中，我们建议扩展这些研究，以评估uMUC1在广泛的癌症诊断和治疗反应中的预测性，考虑到它在超过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、邻近的正常和恶性临床组织样本中确定uMUC1与其他腺癌(胰腺癌、结直肠癌和卵巢癌)的相关性来完成。接下来，我们将使用表达人uMUC1的胰腺癌、结直肠癌和卵巢癌的动物模型，测试我们是否可以通过定量跟踪uMUC1肿瘤抗原的相对丰度来使用我们的成像方法预测和监测恶性转化。与我们最初的应用一样，对于MR成像和uMUC1靶向，我们将使用肿瘤特异性造影剂(MN-EPPT)，该造影剂由针对uMUC1的氧化铁纳米颗粒(MN，可通过磁共振成像检测)与多肽(EPPT)结合而成。最后，我们将通过在已建立的动物模型中进行治疗研究，评估uMUC1作为化疗反应预测生物标志物的全球相关性。我们期望在化疗期间MN-EPPT蓄积的基础上，通过MRI监测肿瘤大小改变之前，观察uMUC1可用性的变化。这将与肿瘤分期相关，也与化疗成功有关，如相对存活率和诱导肿瘤细胞凋亡的定义。

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.