Advancing Cancer Therapy through Ground Breaking Research in Radiation Biology

通过放射生物学的突破性研究推进癌症治疗

• 批准号: 8956241
• 负责人: David Guy Kirsch
• 金额: $ 94.28万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-04 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8956241
• 关键词: Acute; Advanced Malignant Neoplasm; Adverse effects; Cancer Patient; Caring; Cells; Clinic; Complex; Dose; Foundations; Gene-Modified; Genetically Engineered Mouse; Late Effects; Lead; Malignant Neoplasms; Malignant neoplasm of lung; Mission; Modality; Modeling; Molecular; National Cancer Institute; Patient Schedules; Patients; Play; Productivity; Public Health; Radiation; Radiation therapy; Radiobiology; Research; Research Support; Role; Soft tissue sarcoma; Stromal Cells; System; Tamoxifen; Technology; cancer therapy; improved; innovation; insight; mouse model; neoplastic cell; novel; novel strategies; public health relevance; radiation response; recombinase; tumor; tumor microenvironment; tumorigenesis

 DESCRIPTION (provided by applicant): Radiation therapy is utilized to treat over 50% of all patients with cancer. Although radiation therapy plays a critical role in curing some cancer patients and palliating others, a fundamental gap in improving the efficacy of radiation therapy exists because the mechanisms by which radiotherapy controls tumors and causes side effects remain poorly understood. Previously, we used Cre recombinase to generate mouse models to study mechanisms of acute and late effects of radiation. Here, we will apply these models to dissect the molecular mechanism regulating the alpha/beta ratio, which is frequently used in the clinic to select radiation doses and schedules for patients, but currently lacks a molecular rationale. Moreover, we have used Cre recombinase to develop genetically engineered mouse models of soft tissue sarcoma and lung cancer to study radiation biology. To study the complex interactions of tumor stroma and parenchymal cells during radiation therapy, we have recently 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 the tumor stroma. Utilizing Flp and Cre recombinases (i.e. dual recombinase technology) to study the tumor microenvironment's impact on radiation therapy is highly innovative because primary cancers can be initiated with one recombinase, while the other recombinase can be utilized to specifically modify stromal cells. In addition, we have recently generated novel genetically engineered mice in which Flp recombinase activates CreER expression. Therefore, with our novel system Flp initiates tumorigenesis and the tumor cells express CreER so that tamoxifen can modify genes specifically in tumor cells after the tumor has developed. We will use this system to study cell autonomous mechanisms that regulate tumor response to radiation therapy. Advancing the care of cancer patients with discoveries in radiation biology is ambitious, but with our track record of productivity and high impact research, we are poised to use our innovative mouse models to make discoveries that will lay the foundation for novel approaches to improve the efficacy of radiation therapy.

 描述（通过应用提供）：放射治疗可用于治疗所有癌症患者的50％以上。尽管放射疗法在携带某些癌症患者并姑息其他患者中起着至关重要的作用，但由于放射疗法控制肿瘤的机制并导致副作用仍然很少了解，因此存在提高放射治疗的有效性方面的基本差距。以前，我们使用CRE重组酶来生成小鼠模型来研究辐射的急性和后期作用的机制。在这里，我们将应用这些模型来剖析分子机制调节α/β的比率，α/β比率经常在诊所中用于为患者选择辐射剂量和时间表，但目前缺乏分子原理。此外，我们已经使用CRE重组酶开发了软组织肉瘤和肺癌的基因工程小鼠模型来研究放射生物学。为了研究放射治疗期间肿瘤基质和副群细胞的复杂相互作用，我们最近产生了新型的基因工程小鼠菌株，其中可以用FLP重组酶产生原发性癌症。在该系统中，CRE重组酶仍然可以用于在肿瘤基质中专门修饰基因。利用FLP和CRE重组酶（即双重重组酶技术）研究肿瘤微环境对放射治疗的影响具有很高的创新性，因为可以用一种重物组织酶启动原发性癌症，而另一种重物组织酶可以用来特异性地修饰间隙细胞。此外，我们最近生成了新型的基因工程小鼠，其中FLP重组酶激活了CRER表达。因此，借助我们的新系统，FLP启动了肿瘤发生，肿瘤细胞表达crer，以便在肿瘤发生后，他莫昔芬可以在肿瘤细胞中专门修饰基因。我们将使用该系统研究调节肿瘤对放射治疗的反应的细胞自主机制。推进对放射线生物学发现的癌症患者的护理是雄心勃勃的，但是凭借我们的生产力和高影响研究的追踪记录，我们被毒死了使用创新的小鼠模型来创造发现，这将为提高放射治疗效率的新方法奠定基础。