Defining the cellular target of radiotherapy in primary mouse models of cancer

描述（由申请人提供）：人类癌症在由血管、成纤维细胞和免疫细胞组成的复杂环境中发展。肿瘤微环境有助于癌症的发展、进展和对治疗的反应。近三分之二的癌症患者在患病期间接受放射治疗。虽然超过75%的这些患者接受治疗的目的是治愈，但目前仍不清楚放射治疗是否能治愈肿瘤。 杀死肿瘤实质细胞或支持基质细胞如内皮细胞。本研究的长期目标是确定放射治疗肿瘤的机制，以提高放射治疗在临床上的疗效。本申请的总体目标是在原发性癌症小鼠模型中确定放射治疗的细胞靶点。利用两种高效的位点特异性重组酶Cre和Flp，可以同时突变肿瘤实质细胞和基质细胞中特异性的不同基因。这种双重重组酶技术能够通过使参与DNA损伤修复和细胞凋亡的基因突变来操纵原发性肿瘤中肿瘤实质或肿瘤微环境的放射敏感性。这项研究的中心假设是，放射治疗通过杀死肿瘤实质细胞而不是内皮细胞来治愈肿瘤。使用micro-CT靶向照射和原发性肺腺癌和软组织肉瘤的基因工程小鼠模型，将完成以下具体目标：目标1：确定内皮细胞对肿瘤对放射治疗反应的贡献。目的2：确定肿瘤实质细胞对肿瘤放疗反应的贡献。通过选择性敏化或保护肿瘤实质细胞或内皮细胞，将确定原发性癌症放射治疗的关键靶点（）。评估肿瘤微环境对肿瘤对放射治疗的反应的贡献将有助于确定靶向基质细胞的活力，以提高临床放射治疗的疗效。

DESCRIPTION (provided by applicant): Human cancers develop in a complex environment composed of blood vessels, fibroblasts, and immune cells. The tumor microenvironment contributes to cancer development, progression, and response to therapy. Nearly two-thirds of all cancer patients receive radiation therapy during their illness. Although greater than 75% of these patients are treated with the intent to cure, it remains unclear if radiation cures tumors by killing tumor parenchymal cells or supporting stromal cells such as endothelial cells. The long-term goal of this study is to determine the mechanisms of tumor cure by radiation to enhance the efficacy of radiation therapy in the clinic. The overall objective of this application is to deine the cellular target(s) of radiation therapy in primary mouse models of cancer. Utilizing the two highly efficient site-specific recombinases, Cre and Flp, it is possible to contemporaneously mutate different genes specifically in tumor parenchymal cells and stromal cells. This dual recombinase technology enables the radiosensitivity of either the tumor parenchyma or the tumor microenvironment to be manipulated in primary tumors by mutating genes involved in DNA damage repair and apoptosis. The central hypothesis of this study is that radiation therapy cures tumors by killing tumor parenchymal cells rather than endothelial cells. Using micro-CT targeted irradiation and genetically engineered mouse models of primary lung adenocarcinoma and soft tissue sarcoma, the following specific aims will be completed: Aim 1: Determine the contribution of endothelial cells to tumor response to radiotherapy. Aim 2: Determine the contribution of tumor parenchymal cells to tumor response to radiotherapy. By selectively sensitizing or protecting either tumor parenchymal cells or endothelial cells, the critical target() of radiation therapy in primary cancers will be defined. Evaluating the contribution of the tumor microenvironment to tumor response to radiation therapy will help determine the viability of targeting stromal cells to improve the efficacy of radiation therapy in the clinic.