Modulation of Therapeutic Response

治疗反应的调节为了改善癌症的治疗，对放射损伤的调节已经引起了相当大的关注。该项目的主要目标是定义和理解肿瘤生理学的这些方面，包括最终确定肿瘤本质的细胞和分子过程，从而使特定剂量的电离辐射在使用时更有效。实现这一目标的一种方法是研究电离辐射与各种化疗和分子靶向药物的相互作用，以评估是否可以使肿瘤更敏感。我们目前的重点是氟化酮。Halofuginone是一种TGF β的抑制剂，对多种不同类型的人类肿瘤细胞系表现出细胞毒性和放射致敏性。这种药剂特别令人感兴趣的是，halofuginone已被证明可以防止正常组织中辐射引起的晚期效应。我们已经证明，卤仿酮不能保护SCC肿瘤免受辐射诱导的再生延迟。我们的临床前研究支持这一概念，即卤富酮将提供正常组织的选择性放射保护，可能对肿瘤敏感。该项目的另一个主要目标是开发功能成像技术，以更好地表征肿瘤微环境中可能阻止或减少影响辐射反应的药物的重要因素。众所周知，缺氧是辐射敏感性的主要决定因素。因此，我们正在使用几种小鼠肿瘤模型来研究肿瘤缺氧。我们的方法是使用当前的侵入性技术，并将信息扩展到正在开发的非侵入性方法，这样患者的肿瘤治疗概况就可以在个体的基础上进行优化。利用放射生物学分支开发的新型磁共振成像设备（EPR），我们最近表明可以评估小鼠的非侵入性组织氧浓度。三维氧图像可以在不到3分钟的时间内获得，氧分辨率为0.5 mm。我们的EPR非侵入性功能成像方法将增强我们更好地了解肿瘤微环境的能力，并制定有效攻击当前限制癌症治疗方式有效性的潜在障碍的策略。

Modulation of Therapeutic ResponseIn the interest of improving cancer treatment, considerable attention has been placed on the modification of radiation damage. The major goal of this project is to define and understand those aspects of tumor physiology, including cellular and molecular processes that ultimately define the very nature of a tumor such that a particular dose of ionizing radiation, when used will be more effective. One means to that end is to investigate the interaction of ionizing radiation with a variety of chemotherapy and molecularly targeted agents to assess if tumors can be made more sensitive. Our current focus is on halofuginone. Halofuginone, an inhibitor of TGF beta, exhibits cytotoxicity and radiosensitization to a variety of different types of human tumor cell lines. This agent is of particular interest in that halofuginone has been shown to protect against radiation-induced late effects in normal tissues. We have shown that halofuginone does not protect SCC tumors against radiation-induced regrowth delay. Our pre-clinical studies support the concept that halofuginone will provide selective radioprotection of normal tissues with perhaps sensitization of tumor. Another major goal of this project is to develop functional imaging techniques to better characterize factors important in the tumor microenvironment that may prevent or diminish agents from impacting radiation response. It is well established that hypoxia is a major determinant of radiation sensitivity. Therefore, we are using several murine tumor models to study tumor hypoxia. Our approach is to use current invasive techniques and extend that information to non-invasive methods that are under development, such that patient tumor treatment profiles may optimized on an individual basis. Using novel magnetic resonance imaging equipment (EPR) developed in the Radiation Biology Branch we have recently shown that non-invasive tissue oxygen concentration can be evaluated in mice. Three-dimensional oxygen images can be acquired in less than 3 minutes with oxygen resolution to 0.5 mm. Our EPR non-invasive functional imaging approaches should enhance our ability to better understand the tumor microenvironment and develop strategies to effectively attack potential barriers that currently limit the effectiveness of cancer treatment modalities.