Modulation of Therapeutic Response

治疗反应的调节

• 批准号: 7066825
• 负责人: JAMES B MITCHELL
• 金额: --
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7066825
• 关键词: antineoplastics; cell line; combination cancer therapy; drug screening /evaluation; hypoxia; laboratory mouse; magnetic resonance imaging; neoplasm /cancer chemotherapy; neoplasm /cancer radiation therapy; neoplastic growth; oxygen transport; paclitaxel; radiation sensitivity; radiation therapy dosage; radiosensitizer; technology /technique development; tissue /cell culture; transforming growth factors

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.

治疗反应的调节为了改善癌症治疗，相当多的注意力已经放在辐射损伤的修饰上。该项目的主要目标是定义和理解肿瘤生理学的这些方面，包括最终定义肿瘤本质的细胞和分子过程，以便使用特定剂量的电离辐射时更有效。为此目的的一种手段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。我们目前的重点是常山酮。常山酮是TGF β的抑制剂，对多种不同类型的人肿瘤细胞系表现出细胞毒性和放射增敏作用。该药剂特别令人感兴趣，因为已经显示常山酮在正常组织中保护免受辐射诱导的晚期效应。我们已经证明，常山酮不能保护SCC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，即常山酮将提供正常组织的选择性辐射保护，可能与肿瘤增敏。此外，我们已经表明，pheonoxodiol是一种有效的辐射敏化剂，我们目前正在进行机制和动物研究，以进一步表征这种代理。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重要的因素，这些因素可能会阻止或减少影响辐射反应的药物。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，并将这些信息扩展到正在开发的非侵入性方法，以便可以在个体基础上优化患者的肿瘤治疗方案。利用放射生物学分支开发的新型磁共振成像设备（EPR），我们最近表明可以在小鼠中评估非侵入性组织氧浓度。为了将我们的EPR氧成像数据与其他氧成像技术进行比较，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，Cu-64-ATSM和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，但考虑到这两种药物目前都在临床试验中以确定患者的肿瘤缺氧，这些数据很重要。我们的EPR非侵入性功能成像方法应该提高我们更好地了解肿瘤微环境的能力，并制定策略，以有效地攻击目前限制癌症治疗方式有效性的潜在障碍。