Modulation of Therapeutic Response

治疗反应的调节为了改善癌症治疗，辐射损伤的调节受到了相当大的关注。该项目的主要目标是定义和了解肿瘤生理学的那些方面，包括最终确定肿瘤本质的细胞和分子过程，以便特定剂量的电离辐射在使用时将更加有效。为此，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变得更敏感。我们目前的关注点是常青藤酮。常青酮是一种转化生长因子β的抑制剂，对多种不同类型的人类肿瘤细胞具有细胞毒性和放射增敏作用。这种药剂特别令人感兴趣的是，在正常组织中，已有证据表明，常青藤酮可防止辐射引起的迟发效应。我们已经证明，常青酮不能保护鳞状细胞癌肿瘤免受辐射诱导的再生长延迟。我们的临床前研究支持这样的概念，即常青藤酮可能通过对肿瘤的增敏来为正常组织提供选择性的辐射保护。此外，我们已经证明苯氧二醇是一种有效的辐射增敏剂，目前我们正在进行机理和动物研究，以进一步表征这种试剂。该项目的另一个主要目标是开发功能成像技术，以更好地表征在肿瘤微环境中重要的因素，这些因素可能防止或减少药物对辐射反应的影响。众所周知，低氧是辐射敏感性的一个主要决定因素。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，并将这些信息扩展到正在开发的非侵入性方法，以便患者的肿瘤治疗方案可以根据个人情况进行优化。利用放射生物学分部开发的新型磁共振成像设备(EPR)，我们最近已经证明，可以在小鼠身上评估非侵入性组织氧浓度。为了将我们的EPR氧气成像数据与其他氧气成像技术进行比较，我们使用放射性低氧特异性探针进行了一系列小动物PET研究。初步数据表明，无论是铜--ATSM还是F18-MISO都不能准确测量肿瘤氧合的变化。这些数据虽然与我们的EPR数据相比没有用处，但考虑到这两种药物目前都处于临床试验中，以确定患者的肿瘤缺氧情况，这些数据是重要的。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，并开发有效地攻击目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. Additionally we have shown that pheonoxodiol is a potent radiation sensitizer and we are presently conducting mechanistic and animal studies to further characterize this agent. 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. In order to compare our EPR oxygen imaging data with other oxygen imaging techniques, we conducted a series of small animal PET studies using radioactive hypoxic-specific probes. Preliminary data indicate that neither Cu-64-ATSM nor F18-Miso accurately measure changes in tumor oxygenation. These data, while not useful to compare to our EPR data are important given that both agents are currently in clinical trials to determine tumor hypoxia in patients. 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.