An in vivo Screen for Radiation Sensitizers

辐射敏化剂的体内筛选

• 批准号: 7199477
• 负责人: Tin Tin Su
• 金额: $ 18.14万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7199477
• 关键词: Aftercare; Angiogenesis Inhibitors; Apoptosis; Biological Assay; CHES1 gene; Cancer Model; Cancer cell line; Caring; Cell Proliferation; Cells; Cellular biology; Cisplatin; Colorado; Combination Chemotherapy; Developmental Therapeutics Program; Disease; Disease regression; Dose; Drosophila genus; Drosophila melanogaster; Effectiveness; Environment; Gefitinib; Goals; Growth; Growth Factor; Head and Neck Cancer; Head and Neck Neoplasms; Heart; Human; Ionizing radiation; Legal patent; Malignant Neoplasms; Mammals; Mediating; Methods; Microtubules; Modeling; Monitor; Morbidity - disease rate; Mus; National Cancer Institute; Normal tissue morphology; Organ; Outcome; Patients; Pharmaceutical Preparations; Poison; Radiation; Radiation Tolerance; Radiation therapy; Radiation-Sensitizing Agents; Radiosensitization; Receptor Protein-Tyrosine Kinases; Research Personnel; Resistance; Screening procedure; Signal Pathway; Signal Transduction; Standards of Weights and Measures; TP53 gene; Testing; Therapeutic; Time; Tin; Tissues; Toxic effect; Translating; Tumor Suppressor Proteins; Universities; Xenograft procedure; base; cancer cell; cell killing; chemotherapeutic agent; combinatorial; fly; improved; in vivo; in vivo Model; irradiation; mutant; novel; radiation effect; response; small molecule; small molecule libraries; tool; tumor; tumor growth

DESCRIPTION (provided by applicant): Our long-term goal is to rapidly and efficiently identify novel molecules that eradicate head and neck cancers when applied alone and in conjunction with ionizing radiation. The goal for this R21 Exploratory proposal is to establish an efficient, unbiased screening method that will identify radiation sensitizers in a true in vivo setting. Head and neck cancers (HNC) remain extremely difficult to control even with high doses of radiation. Combinations of chemotherapy and radiotherapy have improved local-regional control and patient survival, but at the expense of morbidity. Current focus is on exploring new combinatorial therapies that perturb growth and angiogenic signaling pathways in order to optimize the therapeutic ratio (tumor control/normal tissue toxicity), albeit with an empirical approach. Our goal is to screen from the onset for agents that block critical aspects of cancer cell biology and enhance the effectiveness of radiation in a disease setting such as HNC. Cell-based screens fail to recapitulate the precise tumor environment and may therefore miss useful radiosensitizers. Current in vivo models such as xenografts in mice are costly and cumbersome for rapid screening of new compounds. Radiation responses in Drosophila melanogaster show similarities to radiation responses of tumors, and suggest that Drosophila may be an applicable model. For example, ionizing radiation induces p53-mediated apoptosis, but cell proliferation ensues to compensate and to confer resistance and survival of tumors (in mammals) and organ precursors (in fly). Microtubule poisons that interfere with cell proliferation sensitize Drosophila and human tumors to radiation, while growth factor signaling confers resistance to radiation in both Drosophila and human tumors. The usefulness of a Drosophila model as a rapid screening tool for identifying radiation sensitizers that translate to human cancers will be tested in 2 aims. Aim 1 will be to validate the effect of known radiation sensitizers of human HNC models for their ability to sensitize Drosophila to ionizing radiation. Aim 2 will be to identify, through small molecule libraries, radiosensitizers of Drosophila, and determine their ability to radiosensitize human HNC xenografts. Successful completion of this project would establish a novel, rapid and effective primary screen in vivo for radiosensitizers with potential therapeutic value.

描述（由申请人提供）：我们的长期目标是快速有效地识别单独使用并与电离辐射结合使用时消除头颈癌的新型分子。该R21探索性建议的目标是建立一种有效的，公正的筛选方法，该方法将在真实的体内环境中识别辐射敏化器。即使使用高剂量的辐射，头部和颈部癌症（HNC）仍然很难控制。化学疗法和放射疗法的组合可以改善局部区域控制和患者的存活，但以发病率为代价。当前的重点是探索新的组合疗法，这些疗法扰动生长和血管生成信号通路，以优化治疗比率（肿瘤控制/正常组织毒性），尽管采用经验方法。我们的目标是从一开始筛查，以阻止癌细胞生物学关键方面的药物，并在HNC等疾病环境中提高辐射的有效性。基于细胞的筛网未能概括精确的肿瘤环境，因此可能会错过有用的放射效应器。当前的体内模型，例如小鼠的异种移植物，对于快速筛选新化合物而言是昂贵且繁琐的。果蝇中的辐射反应显示与肿瘤的辐射反应相似，并表明果蝇可能是适用的模型。例如，电离辐射会诱导p53介导的细胞凋亡，但随之而来的细胞增殖是为了补偿并赋予肿瘤（哺乳动物）和器官前体（蝇）的耐药性和存活。微管毒物会干扰细胞增殖的果蝇和人类肿瘤对辐射的敏感性，而生长因子信号传导赋予果蝇和人类肿瘤辐射的耐药性。果蝇模型作为识别转化为人类癌症的辐射敏化剂的快速筛选工具的实用性将在两个目标中进行测试。 AIM 1将是验证人类HNC模型的已知辐射敏化剂的影响，以使果蝇对电离辐射敏感。 AIM 2将是通过小分子文库，果蝇的放射增敏剂鉴定，并确定其放射敏感的人类HNC异种移植物的能力。该项目的成功完成将建立一个具有潜在治疗价值的放射增感器的新型，快速有效的原始筛选。