Mouse Cancer Models for Integrated Tissue/Serum Proteomics and Molecular Imaging

用于整合组织/血清蛋白质组学和分子成像的小鼠癌症模型

基本信息

批准号：
7067900
负责人：
SANJIV S GAMBHIR
金额：
$ 41.9万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-12-01 至 2010-11-30
项目状态：
已结题

项目摘要

Nanotechnology has the potential to significantly impact the development of small animal models of cancer including models to test new antineoplastic therapies. In this project we will develop mouse tumor xenoqraft models that will allow us to test if we can combine both tissue/serum nanosensor based proteomic analysis and molecular imaging with targeted fluorescent quantum dots to predict and monitor treatment response with specific therapies. These models are important to the overall vision of this CCNE-TR for which would like to eventually utilize ex vivo nanosensors and in vivo molecular imaging in cancer patients for improving how we predict and monitor response to therapies. In Aim 1 we will optimize small animal optical imaging instrumentation for imaging quantum dots and also work with General Electric Global Research to develop and test a new frequency domain optical imaging instrument. In Aim 2 we will utilize biologically targeted quantum dots developed in Projects 5 and 6 to image tumors in living mice. We will proceed systematically from targeting one known tumor cell surface antigen (CD20 in our lymphoma xenograft model) to targeting several known tumor cell surface antigens (her2/her3/PSCA in our prostate cancer model), before expanding our target range to neovascularization (avp3 Integrin) and extracellular matrix targets (Matrix metalloproteinase 2, MMP2). In Aim 3 we will develop mouse models of lymphoma for testing antineoplastic therapies in order to study changes in proteins at the cell membrane, in the secretome, and in serum. Cell surface and serum proteome will be analyzed by Solid Phase Extraction of Glycoproteins (SPEC) and Liquid Chromatography Mass Spectrometry (SPEG/MS), whereas secretome will be assessed by biotin capture and subsequent cellular functional profiling array for changes that are predictive of response to therapy. We will test two lymphoma therapy models, one xenograft model for human lymphoma mimicking response vs. resistance to Rituxan therapy, and a mouse pre-clinical model of response vs. resistance to targeted inactivation of the MYC oncogene. In Aim 4 we will test a mouse cancer model using the results from the previous three aims in order to determine the utility of integrating ex vivo and in vivo nanotechnologies to determine protein changes in the tissue/serum and to image molecular changes pre and post-therapy. The significance of this work is that it should help set the foundation for using ex vivo nanosensors in clinical trials, to allow development of novel molecular imaging probes for clinical trials, and to improve drug testing in small animal cancer models. This should lead to marked improvement in predicting and monitoring response to therapy in cancer patients.

纳米技术有可能对小动物癌症模型的发展产生重大影响包括测试新抗肿瘤疗法的模型。在这个项目中，我们将开发小鼠肿瘤异种移植物允许我们测试是否可以结合基于组织/血清纳米传感器的蛋白质组学分析的模型以及使用靶向荧光量子点的分子成像来预测和监测治疗反应并配合特定的疗法。这些模型对于 CCNE-TR 的整体愿景非常重要，因为希望最终在癌症患者中利用离体纳米传感器和体内分子成像来改善我们如何预测和监测对治疗的反应。在目标 1 中，我们将优化小动物光学成像用于成像量子点的仪器，并与通用电气全球研究中心合作开发并测试了一种新型频域光学成像仪器。在目标 2 中，我们将利用生物靶向项目 5 和项目 6 中开发的量子点用于对活体小鼠的肿瘤进行成像。我们将系统地进行从靶向一种已知的肿瘤细胞表面抗原（我们的淋巴瘤异种移植模型中的 CD20）到靶向几种已知的肿瘤细胞表面抗原（我们的前列腺癌模型中的 Her2/her3/PSCA），在扩展之前我们的靶标范围包括新生血管（avp3 整合素）和细胞外基质靶标（Matrix 金属蛋白酶 2、MMP2)。在目标 3 中，我们将开发淋巴瘤小鼠模型以测试抗肿瘤药物疗法，以研究细胞膜、分泌组和血清中蛋白质的变化。细胞将通过糖蛋白固相萃取 (SPEC) 和液体萃取来分析表面和血清蛋白质组色谱质谱法 (SPEG/MS)，而分泌蛋白组将通过生物素捕获进行评估以及随后的细胞功能分析阵列，用于预测治疗反应的变化。我们将测试两种淋巴瘤治疗模型，一种是模拟人类淋巴瘤反应的异种移植模型，另一种是模拟人类淋巴瘤反应的异种移植模型。对 Rituxan 疗法的耐药性，以及小鼠临床前反应模型与靶向药物的耐药性 MYC 癌基因失活。在目标 4 中，我们将使用小鼠癌症模型的结果进行测试前三个目标是为了确定将体外和体内纳米技术整合起来的效用确定组织/血清中的蛋白质变化并对治疗前后的分子变化进行成像。这这项工作的意义在于它应该有助于为临床使用离体纳米传感器奠定基础试验，允许开发用于临床试验的新型分子成像探针，并改进药物测试在小动物癌症模型中。这应该会导致预测和监测方面的显着改进癌症患者对治疗的反应。