Modulation of Therapeutic Response

治疗反应的调节

• 批准号: 7331383
• 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/7331383
• 关键词: Modulation; Therapeutic; Response

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. We have recently shown that radiation-induced gene expression profiles differ significantly for cells exposed in vitro versus the same cells growing as a solid tumor in vivo further underscoring the influence of the tumor microenvironment on the radiation response. The interaction of a variety of chemotherapy and/or molecularly targeted agents with radiation is under study to determine if tumors can be made more sensitive or normal tissues more resistant to radiation treatment. Research continues with halofuginone, an inhibitor of TGF beta signaling pathway, which exhibits cytotoxicity and radiosensitization to a variety of different types of human tumor cell lines and protects against radiation-induced late effects in normal tissues in vivo. Importantly we have shown that halofuginone can protect against radiation-induced soft tissue fibrosis even when administered two weeks post-irradiation. Additional agents that block the TGF beta-signaling pathway are being evaluated with the goal of identifying and implementing agents that 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 and normal tissues that may prevent or diminish agents from impacting radiation response. It is well established that hypoxia is a major determinant of radiation sensitivity and that many human tumors are hypoxic. 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. We have demonstrated that placement of lithium phthalocyanine crystals in tissue provides an accurate means of assessing tissue oxygen levels by electron paramagnetic resonance (EPR). Using novel EPR equipment developed in the Radiation Biology Branch we have recently shown that non-invasive tissue oxygen concentration can be evaluated in mice using a specific redox probe contrast agent. 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.

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。我们最近表明，辐射诱导的基因表达谱显着不同的细胞暴露在体外与相同的细胞生长在体内的实体瘤进一步强调了肿瘤微环境对辐射反应的影响。正在研究各种化疗和/或分子靶向药物与放射的相互作用，以确定是否可以使肿瘤对放射治疗更敏感或使正常组织对放射治疗更耐受。对常山酮的研究仍在继续，常山酮是一种TGF β信号通路抑制剂，对各种不同类型的人类肿瘤细胞系表现出细胞毒性和放射增敏作用，并在体内保护正常组织免受辐射诱导的晚期效应。重要的是，我们已经表明，即使在照射后两周给药，常山酮也可以防止辐射诱导的软组织纤维化。正在评估阻断TGF β信号传导途径的其他药物，目的是鉴定和实施对正常组织提供选择性放射保护的药物，可能对肿瘤致敏。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和正常组织中可能阻止或减少影响辐射反应的因子。众所周知，缺氧是辐射敏感性的主要决定因素，并且许多人类肿瘤是缺氧的。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。我们已经证明，酞菁锂晶体在组织中的位置提供了一个准确的手段，评估组织的氧水平的电子顺磁共振（EPR）。使用新的EPR设备开发的放射生物学分支，我们最近表明，非侵入性组织氧浓度可以在小鼠使用特定的氧化还原探针造影剂进行评估。三维氧气图像可以在不到3分钟的时间内获得，氧气分辨率为0.5 mm。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，有效地攻击目前限制癌症治疗方式有效性的潜在障碍。