Multi-Parameter Monitoring of Breast Cancer Progression and Therapeutic Response

描述（由申请人提供）： 随着分子靶向癌症疗法的发展，能够确定其改善患者总体生存率的功效是非常有利的。非侵入性成像技术目前可用于可视化人体的不同病理状况，但由于缺乏肿瘤特异性成像探针，它们用于癌症监测的用途受到限制。我们之前已经开发了一种多模式成像探针（MN-EPPT），靶向糖基化不足的粘蛋白-1肿瘤抗原（uMUC-1），该抗原在超过90%的乳腺肿瘤中过表达和糖基化不足，其表达与肿瘤从癌前病变到晚期恶性肿瘤的进展以及肿瘤对化疗的反应密切相关。在过去，我们已经表明，MN-EPPT是高度特异性的uMUC-1抗原，并证明其潜力的肿瘤检测在各种肿瘤模型和跟踪肿瘤大小的变化化疗后的临床前胰腺癌模型。我们的初步结果进一步扩展了这些发现，定义了一种方法，用于同时定量评估化疗前后乳腺肿瘤的肿瘤体积和靶抗原可用性。在本申请中，我们提出研究在癌变的不同阶段的人乳腺病变中MN-EPPT的差异积累，作为uMUC-1可用性的函数，并利用这种差异积累来非侵入性地和定量地监测肿瘤从癌前病变到早期恶性病变，并最终到晚期恶性病变的进展。我们将监测肿瘤进展的两个参数：1.基于可用于肿瘤描绘的靶向探针的肿瘤选择性摄取的肿瘤体积的变化，以及2.基于MN-EPPT对uMUC-1抗原的特异性的uMUC-1抗原可用性的变化，并表示为肿瘤摄取的探针量的差异。最后，我们将评估常规化疗过程中肿瘤大小和uMUC-1表达的变化，并将其与肿瘤进展/消退沿着从早期到晚期恶性肿瘤的连续体相关联。如果成功，这项研究可以进一步转化为临床应用，因为相关的氧化铁已经在临床试验中进行了测试。

DESCRIPTION (provided by applicant): With the development of molecularly targeted cancer therapies, it is highly advantageous to be able to determine their efficacy to improve overall patient survival. Non-invasive imaging techniques are currently available for visualizing different pathological conditions of the human body, but their use for cancer monitoring is limited due to the lack of tumor-specific imaging probes. We have previously developed a multi-modal imaging probe (MN-EPPT) targeting the underglycosylated mucin-1 tumor antigen (uMUC-1), which is overexpressed and underglycosylated on over 90% of breast tumors and whose expression is tightly linked to tumor progression from pre-malignancy to advanced malignancy, as well as to tumor response to chemotherapy. In the past, we have shown that MN-EPPT is highly specific for uMUC-1 antigen and demonstrated its potential both for tumor detection in a variety of tumor models and for the tracking of change in tumor size following chemotherapy in a pre-clinical pancreatic cancer model. Our preliminary results extend these findings even further by defining a method for the simultaneous quantitative assessment of tumor volume and target antigen availability in breast tumors before and after chemotherapy. In this application, we propose to investigate the differential accumulation of MN-EPPT in human breast lesions at different stages of carcinogenesis, as a function of uMUC-1 availability, and to utilize this differential accumulation in order to noninvasively and quantitatively monitor the progression of the tumor from pre- malignancy to early malignancy, and finally to advanced malignancy. We will monitor two parameters of tumor progression: 1. change in tumor volume based on the tumor-selective uptake of the targeted probe which can be used for tumor delineation and 2. change in uMUC-1 antigen availability based on the specificity of MN- EPPT for the uMUC-1 antigen and expressed as differences in the amount of probe taken up by the tumor. Finally, we will evaluate change in tumor size and uMUC-1 expression during the course of conventional chemotherapy and correlate them with tumor progression/regression along the continuum from early to advanced malignancy. If successful, this study can further be translated into clinical applications, since related iron oxides have already been tested in clinical trials.