Imaging Signaling Changes in Cancer and Treatment

描述(由申请人提供)： 最常见的脑肿瘤是胶质瘤，最常见的恶性变种是多形性胶质母细胞瘤(GBM)。对于这种肿瘤缺乏有效的治疗需要对胶质瘤形成和发展的生物学有更好的了解。最近的研究已经发现了胶质瘤中的异常信号通路，转基因动物模型表明，其中一些信号异常与胶质瘤的形成和发展有关。这项拟议研究的总体目标是在这些最新发现的基础上，开发非侵入性体内报告成像系统，用于研究胶质瘤和其他肿瘤的恶性转化(致癌)，并用于靶向药物治疗的评估。 我们计划开发和验证在转导细胞系和荷瘤动物中通过RAS/Raf/MEK/Erk-和PKB/Akt/mTOR介导的通路对PDGF和EGFR信号进行非侵入性光学和放射性核素成像的方法。这项建议结合了我们机构(E.Holland博士)已建立的胶质瘤转基因动物模型和申请人实验室的分子成像经验。具体地说，我们计划开发用于光学和放射性核素成像的多模式报告系统，该系统将通过一系列体外和体内实验和分子分析进行验证。我们计划开发和研究表达这些报告系统的转基因动物，然后发展双转基因报告动物，以便：1)成像肿瘤发生过程中的异常信号和通路活性；2)成像和监测靶向药物治疗过程中的信号通路活性。开发携带信号转导报告系统的转基因动物的潜在好处是巨大的。一旦开发出来，这些报告系统和携带报告系统的转基因动物可以用于研究不同器官系统的肿瘤形成，也可以用于其他疾病过程的研究。靶向药物治疗期间成像和监测信号转导通路活性的能力为在动物模型中评估药物疗效提供了一种新的方法。这可以在体内进行，而且是非侵入性的，在细胞抑制药物的评估中可能特别有用。

DESCRIPTION (provided by applicant): The most common brain tumors are gliomas, and the most common malignant variant is glioblastoma multiforme (GBM). The absence of effective therapy for this tumor requires a better understanding of the biology of glioma formation and progression. Recent studies have identified abnormal signaling pathways in gliomas and transgenic animal models have shown that some of these signaling abnormalities are causally related to glioma formation and progression. The overall aim of the proposed research is to build on these recent findings and to develop noninvasive in vivo reporter imaging systems that can be used in the study malignant transformation (oncogenesis) of gliomas and other tumors, and for the assessment of targeted drug therapy. We plan to develop and validate methods for non-invasive optical and radionuclide imaging of PDGF and EGFR signaling through the Ras/Raf/MEK/Erk- and PKB/Akt/mTOR-mediated pathways in transduced cell lines and tumor-bearing animals. This proposal combines established transgenic animal models of gliomas that exist at our institution (Dr. E. Holland) with the molecular imaging experience of the applicant's laboratory. Specifically, we plan to develop multi-modal reporter systems for both optical- and radionuclide based imaging that will be validated by a series of in vitro and in vivo experiments and molecular assays. We plan to develop and study transgenic animals expressing these reporter systems, and then develop double-transgenic reporter animals in order to: 1) image aberrant signaling and pathway activity during oncogenesis, and 2) image and monitor signal pathway activity during targeted drug therapy. The potential benefits of developing transgenic animals bearing signal transduction reporter systems are substantial. Once developed, these reporter systems and the transgenic animals bearing the reporter systems can be used to study oncognesis in different organ systems and could be useful in the study of other disease processes as well. The ability to image and monitor signal transduction pathway activity during targeted drug therapy offers a new approach to the assessment of drug efficacy in animal models. This can be performed in vivo and noninvasively, and may be particularly useful in the assessment of cytostatic drugs.