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（由申请人提供）：放射治疗用于治疗超过 50% 的癌症患者，尽管放射治疗在治愈某些癌症患者和缓解其他癌症患者方面发挥着关键作用，但在提高放射治疗的疗效方面仍存在根本性差距，因为。此前，我们利用Cre重组酶构建小鼠模型来研究放射治疗的急性和晚期效应机制，但我们对放射治疗控制肿瘤和引起副作用的机制仍知之甚少。在这里，我们将应用这些模型来剖析调节的分子机制。 α/β比率，在临床上经常用于为患者选择放射剂量和时间表，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。研究放射生物学。为了研究放射治疗过程中肿瘤基质和实质细胞的复杂相互作用，我们最近培育了新的基因工程小鼠品系，其中可以通过 Flp 重组酶 Cre 产生原发性癌症。重组酶仍可用于特异性修饰肿瘤基质中的基因，利用 Flp 和 Cre 重组酶（即双重组酶技术）来研究肿瘤微环境对放射治疗的影响是高度创新的，因为原发性癌症可以用一种重组酶引发，而另一种重组酶则可以引发原发性癌症。重组酶可用于特异性修饰基质细胞。此外，我们最近培育出新型基因工程小鼠，其中 Flp 重组酶可激活 CreER 表达。我们的新系统 Flp 启动肿瘤发生，肿瘤细胞表达 CreER，以便他莫昔芬可以在肿瘤发展后特异性修改肿瘤细胞中的基因，我们将使用该系统来研究调节肿瘤对放射治疗的反应的细胞自主机制。癌症患者在放射生物学方面的发现是雄心勃勃的，但凭借我们在生产力和高影响力研究方面的记录，我们准备使用我们的创新小鼠模型来做出发现，这将为提高放射治疗功效的新方法奠定基础。