Defining the Cellular Target of Radiation Therapy

描述(申请人提供)：放射疗法被用于治疗大约50%的癌症患者。然而，提高放射治疗疗效的一个根本差距是，放射治疗控制肿瘤的机制仍然知之甚少。例如，肿瘤内皮细胞是否是介导肿瘤治愈的放射治疗的关键靶点就存在争议。这项研究的总体目标是确定放射治疗的细胞靶点：肿瘤细胞(这里指肿瘤实质细胞)与 内皮细胞。这一应用的中心假设是放射治疗通过杀死肿瘤实质细胞而不是肿瘤内皮细胞来治愈。为了研究肿瘤内皮细胞和肿瘤实质细胞作为放射治疗靶点的相对贡献，我们产生了新的基因工程小鼠。此前，我们使用Cre重组酶建立肺癌和软组织肉瘤的基因工程小鼠模型，以研究放射生物学。我们现在已经产生了新的基因工程小鼠品系，在其中可以用FLP重组酶产生原发癌。在这个系统中，Cre重组酶仍然可以用来修饰肿瘤内皮细胞中特异的基因。利用FLP和Cre重组酶(即双重组酶技术)研究肿瘤内皮细胞在放射治疗中的作用具有很高的创新性，因为其中一个重组酶可以启动原发癌，而另一个重组酶可以用来特异性地修饰内皮细胞的放射敏感性。这项拟议的研究具有重要意义，因为它将澄清肿瘤内皮细胞是否最终是放射治疗的关键靶点，这些知识有可能为提高放射治疗疗效的新方法奠定基础。

DESCRIPTION (provided by applicant): Radiation therapy is utilized to treat approximately 50% of all patients with cancer. However, a fundamental gap in improving the efficacy of radiation therapy is that the mechanisms by which radiotherapy controls tumors remain poorly understood. For example, it is controversial whether tumor endothelial cells are a critical target of radiation therapy, which mediate tumor cure. The overall goal of this research is to define the cellular target of radiation therapy: tumor cells (referred to here as tumor parenchymal cells) vs. endothelial cells. The central hypothesis of this application is that radiation therapy cures cance by killing tumor parenchymal cells rather than tumor endothelial cells. To study the relative contribution of tumor endothelial cells and tumor parenchymal cells as targets of radiation therapy, we have generated novel genetically engineered mice. Previously, we used Cre recombinase to develop genetically engineered mouse models of lung cancer and soft tissue sarcoma to study radiation biology. We have now generated novel strains of genetically engineered mice in which primary cancers can be generated with Flp recombinase. In this system, Cre recombinase can still be utilized to modify genes specifically in tumor endothelial cells. Utilizing Flp and Cre recombinases (ie dual recombinase technology) to study the role of tumor endothelial cells in radiation therapy is highly innovative because primary cancers can be initiated with one recombinase, while the other recombinase can be utilized to specifically modify the radiosensitivity of the endothelial cells. The proposed research is significant, because it will clarify whether tumor endothelial cells are a critical target for radiation therapy Ultimately, such knowledge has the potential to lay the foundation for novel approaches to improve the efficacy of radiation therapy.