Proj 3: Improving Cancer Therapy using Molecular Imaging

项目3：恶性胶质瘤是一种致命的肿瘤，迫切需要改善我们的 从生物学上了解这些病变，以便合理地开发治疗方法。分子成像可以 用于询问影响其侵袭性表型的复杂致癌途径。 此外，一次有针对性地中断一个或多个信令进程可能会为 提高患者的总体存活率。然而，相互连接的通路可以为肿瘤提供 信号级联中的冗余使其能够适应，从而逃避治疗。此外， 最近的研究表明，胶质瘤还含有一种对治疗有抵抗力的癌症干细胞亚群。 这些细胞可以在常规治疗干预后提供肿块的再繁殖。 因此，在这个项目中，我们寻求一种范式转变，以接近改进治疗的发展 通过开发和整合新的分子成像工具为神经肿瘤科患者制定策略 解决目前阻碍胶质瘤治疗的三个关键方面：(1)未知的影响 抑制其他信号通路上的信号分子以及胶质瘤细胞如何逃避治疗 在互连的信令路径内使用冗余(逃逸路径)(2)这些信令如何 在胶质瘤干细胞群体中的途径不同；(3)我们如何利用这些信息来消除 胶质瘤干细胞群和肿瘤部位内的大量细胞。光学分子成像 关键分子事件的记者，包括Met激酶活性，Akt激酶活性，EGFR活性和 Caspase-3将在人脑胶质瘤细胞中表达，并作为读数用于评估 治疗干预对脑胶质瘤干细胞和非干细胞致癌信号活性的影响 在体外和体内的种群。我们将设计一种人脑胶质瘤细胞系，使其表达CD133 将与生物发光活性相关。这将使我们能够量化 肿瘤干细胞群体。使用核磁共振和肿瘤干细胞监测肿瘤负荷的能力 使用这条工程报道线的人群将导致对小说的识别和验证 其中癌症干细胞依赖的再繁殖被推迟从而改善的治疗/组合 脑肿瘤患者的临床转归。公共卫生：这里建议的研究将提供 将分子成像报告和应用纳入药物开发和应用的基础 评估过程中提高我们对治疗耐药性的认识，这应该导致更多 选择治疗方法的基本原理。总体而言，该项目的成功将导致改善 胶质瘤患者的存活率。

PROJECT 3: Malignant gliomas are uniformly fatal tumors and there is an urgent need for improving our biological understanding of these lesions in order to rationally develop treatments. Molecular imaging can be adopted for interrogating the complex oncogenic pathways which impact their aggressive phenotype. Furthermore, targeted disruption of one or several signaling processes at once may provide an avenue for improving the overall survival of patients. However, the interconnecting pathways can provide tumors with redundancies in the signaling cascades allowing for it to adapt and thereby evade treatment. Moreover, recent studies have shown that gliomas also contain a therapeutically resistant subpopulation of cancer stem cells which can provide for repopulation of the mass following conventional therapeutic interventions. Therefore, in this Project, we seek a paradigm shift in approaching the development of improved therapeutic strategies for neurooncology patients by development and incorporation of novel molecular imaging tools to address three key aspects believed to frustrate current treatment of gliomas: (1) Unknown effects of inhibiting signaling molecules on other signaling pathways and how the glioma cell can evade treatment using redundancies (escape routes) within the interconnected signaling pathways (2) How these signaling pathways differ in the glioma stem cell population and; (3) How we can use this information to eliminate the glioma stem cell population along with the bulk mass of cells within the tumor site. Optical molecular imaging reporters for key molecular events including Met kinase activity, Akt kinase activity, EGFR activity and Caspase-3 will be expressed in human glioma cells and used as readouts for evaluating the response of treatment interventions on the oncogenic signaling activities in the glioma stem and non-stem cell populations both in vitro and in vivo. We will engineer a human glioma cell line such that CD133 expression will correlate with bioluminescence activity. This will enable us to quantify the growth and survival of the tumor stem cell population. The ability to monitor tumor burden using MRI as well as the cancer stem cell population using this engineered reporter line will result in the identification and validation of novel treatments/combinations wherein cancer stem cell dependent repopulation is delayed and thereby improving the clinical outcome of brain tumor patients. Public Health: The studies proposed here will provide the foundation of incorporating molecular imaging reporters and applications into the drug development and evaluation process for improving our understanding treatment resistance which should lead to a more rationale approach for selection of treatments. Overall, the success of this Project will lead to improved survival of patients with gliomas.