An in vivo Screen for Radiation Sensitizers

描述（由申请人提供）：我们的长期目标是在单独应用和与电离辐射结合使用时快速有效地识别根除头颈部癌症的新分子。本R21探索性提案的目标是建立一种有效、公正的筛选方法，以在真实的体内环境中识别辐射致敏物。头颈癌（HNC）即使使用高剂量的辐射也极难控制。化疗和放疗的结合改善了局部区域控制和患者生存，但以发病率为代价。目前的重点是探索新的组合疗法，扰乱生长和血管生成信号通路，以优化治疗比例（肿瘤控制/正常组织毒性），尽管采用经验方法。我们的目标是从发病开始筛选阻断癌细胞生物学关键方面的药物，并增强辐射在HNC等疾病环境中的有效性。基于细胞的筛选不能精确地再现肿瘤环境，因此可能会错过有用的放射增敏剂。目前的体内模型，如小鼠异种移植物，对新化合物的快速筛选既昂贵又繁琐。黑腹果蝇的辐射反应与肿瘤的辐射反应相似，提示果蝇可能是一个适用的模型。例如，电离辐射诱导p53介导的细胞凋亡，但细胞增殖随后补偿并赋予肿瘤（在哺乳动物中）和器官前体（在苍蝇中）的抗性和存活。干扰细胞增殖的微管毒物使果蝇和人类肿瘤对辐射敏感，而生长因子信号则赋予果蝇和人类肿瘤对辐射的抗性。果蝇模型作为一种快速筛选工具，用于识别转化为人类癌症的辐射致敏物，其实用性将在两个目标中进行测试。目的1将验证已知的辐射致敏剂对人类HNC模型的影响，因为它们能够使果蝇对电离辐射敏感。目的2将通过小分子文库鉴定果蝇的放射致敏剂，并确定它们对人类HNC异种移植物放射致敏的能力。该项目的成功完成将为具有潜在治疗价值的放射增敏剂建立一种新颖、快速、有效的体内初级筛查方法。

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.