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: 10064609
• 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/10064609
• 关键词: Acute; Advanced Malignant Neoplasm; Cancer Patient; Cells; Clinic; Complex; Enterobacteria phage P1 Cre recombinase; FLP recombinase; Foundations; Genes; 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 Dose Unit; Radiation therapy; Radiobiology; Research; Research Support; Role; Soft tissue sarcoma; Stromal Cells; System; Tamoxifen; Technology; cancer care; cancer therapy; improved; innovation; insight; mouse model; neoplastic cell; novel; novel strategies; palliate; public health relevance; radiation effect; radiation response; recombinase; side effect; 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(申请人提供)：放射治疗被用于治疗超过50%的癌症患者。尽管放射治疗在治愈一些癌症患者和缓解其他癌症患者方面发挥了关键作用，但在提高放射治疗的疗效方面存在着一个根本性的差距，因为放射治疗控制肿瘤和引起副作用的机制仍然知之甚少。以前，我们使用Cre重组酶建立小鼠模型来研究辐射急性和晚期效应的机制。在这里，我们将应用这些模型来剖析调节α/β比率的分子机制，该比率在临床上经常用于选择患者的辐射剂量和治疗方案，但目前缺乏分子基础。此外，我们还利用Cre重组酶建立了软组织肉瘤和肺癌的基因工程小鼠模型，以研究放射生物学。为了研究肿瘤间质和实质细胞在放射治疗过程中的复杂相互作用，我们最近培育了新的基因工程小鼠品系，在其中可以用FLP重组酶产生原发癌。在这个系统中，Cre重组酶仍然可以用来修饰肿瘤间质中特异的基因。利用FLP和Cre重组酶(即双重组酶技术)研究肿瘤微环境对放射治疗的影响具有很高的创新性，因为其中一个重组酶可以启动原发癌，而另一个重组酶可以用来特异性地修饰基质细胞。此外，我们最近培育了一种新型的基因工程小鼠，在这种小鼠中，FLP重组酶激活了Creer的表达。因此，在我们的新系统中，FLP启动肿瘤形成，肿瘤细胞表达Creer，因此他莫昔芬可以在肿瘤发生后特异性地修改肿瘤细胞中的基因。我们将使用这个系统来研究调节肿瘤对放射治疗反应的细胞自主机制。通过辐射生物学的发现推动癌症患者的护理是雄心勃勃的，但凭借我们在生产力和高影响力研究方面的记录，我们准备利用我们的创新小鼠模型做出发现，为提高放射治疗效率的新方法奠定基础。