Molecular-Specific Detection of Tumors: MRI Investigations

描述（由申请人提供）：该项目的重点是开发和评估用于体内检测肿瘤抗原的新型肿瘤抗原特异性磁共振成像（MRI）分子探针，这些探针可作为早期检测人类恶性肿瘤的诊断生物标志物。将使用转基因小鼠肝癌发生模型来跟踪肿瘤结节、腺瘤和癌发展期间的顺序变化。这项研究将有助于在体内检测恶性肿瘤形成的诊断方法的发展。具体而言，我们计划测试肿瘤特异性抗原MRI分子靶向剂的体内特异性，以便能够通过在小鼠肝脏肿瘤模型的实验性致癌的各个阶段中靶向与肿瘤恶性相关的抗原来检测并逐步跟踪肿瘤的形成。具体目标1：在小鼠肝癌细胞培养模型中确定新型MRI分子靶点对肿瘤抗原的特异性：目的1：使用针对恶性肿瘤特异性肿瘤抗原的抗体的免疫组织化学确定恶性肿瘤特异性肿瘤抗原在小鼠肝癌细胞系（BW 1 J、HEPA 1-6或MH-224）中的表达程度。目标二：开发肿瘤抗原特异性MRI造影剂（含钆（Gd）或氧化铁母体化合物），标记有针对恶性肿瘤特异性肿瘤抗原的抗结节/肿瘤标志物抗体（Ab）。目标三：利用MRI初步确定抗原特异性造影剂在体外对不同小鼠肝癌细胞系抗原结合特异性的有效性。具体目标2：抗原特异性MRI造影剂在小鼠实验性肿瘤模型中的体内检测：目的4：抗原特异性MRI造影剂在实验性啮齿动物肿瘤模型中的体内检测和预测肿瘤的形成。目标5：比较活体MRI检测肿瘤特异性分子标志物与常规小鼠肝切片活检检测恶性肿瘤特异性抗原及肿瘤分级的差异。一旦我们在小鼠肝癌发生模型中建立了最佳的分子靶向剂，则为启动人类细胞和计划肝癌患者的临床评估奠定了基础。

DESCRIPTION (provided by applicant): This project is focussed on developing and assessing novel tumor antigen-specific magnetic resonance imaging (MRI) molecular probes for the in vivo detection of tumor antigens, which may serve as diagnostic biomarkers for early detection of malignant human cancers. A transgenic mouse hepatocarcinogenesis model will be used to follow sequential changes during neoplastic nodule, adenoma and carcinoma development. This research will aid in the development of diagnostic methods for in vivo detection of malignant tumor formation. Specifically, we plan to test the in vivo specificity of tumor-specific antigen MRI molecular targeting agents to be able to detect and progressively follow the formation of tumors by targeting antigens associated with tumor malignancy during various stages of experimental carcinogenesis in a mouse liver tumor model. SPECIFIC AIM 1: To determine the specificity of novel MRI molecular targets for tumor antigens in mouse hepatoma cell culture models: Objective 1: Determine the degree of expression of malignant-specific tumor antigens in mouse hepatoma cell lines (BW1J, HEPA 1-6 or MH-224) using immunohistochemistry with antibodies specific for the malignant-specific tumor antigens. Objective 2: Develop tumor antigen specific MRI contrast agents (with gadolinium (Gd) or iron oxide parent compounds) tagged with an anti-nodule/tumor marker antibody (Ab) specific for malignant-specific tumor antigens. Objective 3: To use MRI to initially determine the effectiveness of the antigen-specific contrast agents for antigen-binding specificity in various mouse hepatocellular carcinoma cell lines in vitro. SPECIFIC AIM 2: Use antigen specific MRI contrast agents to detect tumor antigens in vivo within experimental mouse carcinogenesis models: Objective 4: Use antigen specific MRI contrast agents to detect and predict the formation of tumors in vivo in experimental rodent carcinogenesis models. Objective 5: To compare in vivo MRI detection of tumor-specific molecular markers with conventional immunohistoehemistry of mouse liver slices for malignant-specific tumor antigens, and tumor grading. Once we have established the optimal molecular-targeting agent in a mouse hepatocarcinogenesis model, then the groundwork is established for initiation of human cell and planning of clinical evaluations for patients with liver cancer.