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

在原代小鼠癌症模型中定义放疗的细胞靶点

• 批准号: 8526641
• 负责人: Everett James Moding
• 金额: $ 3.94万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8526641
• 关键词: Adenoviruses; Adjuvant Therapy; Apoptosis; Blood Vessels; Cancer Patient; Cell Death; Cells; Cessation of life; Clinic; Clinical; Complex; DNA Damage; DNA Double Strand Break; DNA Repair; Development; Endothelial Cells; Environment; Fibroblasts; Genes; Genetically Engineered Mouse; Germ Cells; Goals; Human; Immune; In Vitro; Knowledge; Lead; Lung Adenocarcinoma; Malignant Neoplasms; Mediating; Mission; Molecular; Mutate; Patients; Primary Neoplasm; Probability; Public Health; Radiation; Radiation Tolerance; Radiation therapy; Research; Site; Stromal Cells; Targeted Radiotherapy; Technology; Therapeutic; cadherin 5; cancer therapy; cell type; cellular targeting; design; improved; in vivo; innovation; insight; irradiation; killings; mouse model; neoplastic cell; next generation; public health relevance; recombinase; response; sarcoma; soft tissue; tumor; tumor growth; tumor microenvironment

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.

描述(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生、发展和对治疗的反应。近三分之二的癌症患者在患病期间接受了放射治疗。尽管这些患者中超过75%的人是出于治愈的目的而接受治疗，但目前尚不清楚放射是否通过 杀伤肿瘤实质细胞或支持内皮细胞等间质细胞。本研究的长期目标是确定放射治疗肿瘤的机制，以提高临床放射治疗的疗效。这项应用的总体目标是确定放射治疗的细胞靶点(S)在初级小鼠癌症模型中。利用Cre和FLP这两种高效的位点特异性重组酶，可以同时突变肿瘤实质细胞和间质细胞中的不同基因。这种双重重组技术使肿瘤实质或肿瘤微环境的放射敏感性能够通过突变与DNA损伤修复和细胞凋亡有关的基因在原发肿瘤中被操控。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疗肿瘤。利用Micro-CT靶向照射和基因工程小鼠的原发肺腺癌和软组织肉瘤模型，将完成以下具体目标：目的1：确定血管内皮细胞在肿瘤放疗反应中的作用。目的2：确定肿瘤实质细胞在肿瘤放疗反应中的作用。通过选择性地敏化或保护肿瘤实质细胞或血管内皮细胞，将确定原发性癌症放射治疗的关键靶点。评价肿瘤微环境对肿瘤放射治疗反应的贡献将有助于确定靶向基质细胞的活性，从而提高临床放射治疗的疗效。