Dissecting the role of the immune system in the radiation response of Kras-mutant tumors

剖析免疫系统在 Kras 突变肿瘤放射反应中的作用

• 批准号: 9395705
• 负责人: Amy Jordan Wisdom
• 金额: $ 3.53万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9395705
• 关键词: Affect; Alpha Cell; Automobile Driving; Cancer Burden; Cancer Model; Cancer Patient; Caring; Cells; Clinic; Clinical; Cre-LoxP; Data; Flow Cytometry; Gene Expression Profiling; Genetic; Genetically Engineered Mouse; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; High-Risk Cancer; Human; Immune; Immune Evasion; Immune Targeting; Immune response; Immune system; Immunosuppressive Agents; Immunotherapy; Interleukin-10; Interleukin-6; Ionizing radiation; KRAS2 gene; Knowledge; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Mediating; Mission; Modeling; Molecular; Mus; Mutation; Myelogenous; Myeloid Cells; Non-Small-Cell Lung Carcinoma; Oncogenic; Pathway interactions; Patients; Phenotype; Play; Public Health; RANTES; Radiation; Radiation Tolerance; Radiation therapy; Recruitment Activity; Rectal Cancer; Recurrence; Research; Resistance; Role; Signal Transduction; Soft tissue sarcoma; Technology; Testing; Treatment Failure; Work; cancer cell; cancer type; clinically significant; high risk; improved; in vivo; insight; mouse model; mutant; novel; outcome forecast; radiation resistance; radiation response; radioresistant; sarcoma; tumor; tumor growth; tumor microenvironment

ABSTRACT: RAS mutations occur in one-third of all human cancers and confer a poor prognosis with a high risk of recurrence. Oncogenic KRAS mutations are particularly common among non-small cell lung cancer and pancreatic cancer, which are frequently treated with radiation therapy. These genetic alterations have been associated with radiation resistance, which often contributes to therapy failure for these common malignancies. The underlying mechanism by which KRAS-mediated resistance to ionizing radiation occurs is poorly understood, but has been proposed to be mediated via a cell-autonomous signaling mechanism. Using genetically engineered mouse models of primary soft tissue sarcomas, my preliminary data demonstrate that Kras-mutant tumors respond poorly to radiation compared to Kras wild-type tumors in an immune system- dependent manner. To understand the role of myeloid cells in the radiation response of Kras-mutant tumors, I will apply Cre-LoxP technology to generate Kras-mutant and Kras-wild type tumors while manipulating specific subsets of myeloid cells. The long-term goal of this project is to elucidate and harness mechanisms of radiation resistance to enhance the efficacy of radiation therapy in the clinic. The primary objective of this project is to dissect the role of immune cells in the radiation response of Kras-driven tumors by genetically manipulating myeloid cells. By improving our understanding of the role of Kras mutations in the immune response to radiation therapy, a critical mechanism of radiation resistance will be defined. Evaluating the role of the immune system in the radiation response of primary cancers will help determine the viability of targeting the immune system to improve the efficacy of radiation therapy in the clinic.

摘要： 三分之一的人类癌症中存在RAS突变，预后不良，且发生癌症的风险很高 复发致癌性KRAS突变在非小细胞肺癌中特别常见， 胰腺癌，通常用放射疗法治疗。这些基因改变 与辐射抗性相关，这通常导致这些常见恶性肿瘤的治疗失败。 KRAS介导的电离辐射抗性发生的潜在机制很差， 理解，但已提出通过细胞自主信号传导机制介导。使用 原发性软组织肉瘤的基因工程小鼠模型，我的初步数据表明， 与免疫系统中的Kras野生型肿瘤相比，Kras突变型肿瘤对辐射的反应较差- 依赖的方式。为了了解髓系细胞在Kras突变型肿瘤放射反应中的作用，我 将应用Cre-LoxP技术产生Kras突变型和Kras野生型肿瘤，同时操纵特异性 骨髓细胞的亚群。 本项目的长期目标是阐明和利用抗辐射机制， 放射治疗在临床上的疗效。本项目的主要目标是剖析 免疫细胞在Kras-driven肿瘤的辐射反应通过遗传操纵骨髓细胞。通过 提高我们对Kras突变在放射治疗免疫反应中的作用的理解， 将定义抗辐射的关键机制。评估免疫系统在免疫系统中的作用 原发性癌症的辐射反应将有助于确定靶向免疫系统的可行性， 提高临床放射治疗的疗效。