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（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。在所有癌症患者患病期间，将近三分之二的癌症患者接受放射治疗。尽管这些患者中有75％的治疗方法是治愈的目的，但尚不清楚辐射是否可以通过 杀死肿瘤实质细胞或支撑基质细胞，例如内皮细胞。这项研究的长期目标是通过辐射确定肿瘤治疗的机制，以增强诊所的辐射疗法的功效。该应用的总体目的是在癌症主要小鼠模型中定位放射治疗的细胞靶标。利用两个高效的位点特异性重组酶CRE和FLP，可以同时突变在肿瘤实质细胞和基质细胞中的不同基因。这种双重重组酶技术使肿瘤实质或肿瘤微环境的放射敏感性通过突变与DNA损伤修复和凋亡相关的基因来操纵。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。使用微CT的靶向辐射和原发性肺腺癌和软组织肉瘤的基因工程小鼠模型，将完成以下特定目标：AIM 1：确定内皮细胞对肿瘤对放射治疗的反应的贡献。目标2：确定肿瘤实质细胞对肿瘤对放射疗法的反应的贡献。通过选择性化或保护肿瘤实质细胞或内皮细胞，将定义原发性癌症中放射治疗的关键靶（）。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提高诊所放射治疗功效的可行性。