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。我们最近发现，在体外暴露的细胞与在体内作为实体肿瘤生长的相同细胞，辐射诱导的基因表达谱显着不同，进一步强调了肿瘤微环境对辐射反应的影响。各种化疗和/或分子靶向药物与辐射的相互作用正在研究中，以确定是否可以使肿瘤更敏感，或使正常组织对放射治疗更具抵抗力。研究继续使用转化生长因子β信号通路的抑制剂常青酮，它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，并在体内正常组织中保护免受辐射诱导的迟发效应。重要的是，我们已经证明，即使在照射后两周给药，常青藤酮也可以预防辐射诱导的软组织纤维化。目前正在对其他阻断转化生长因子β信号通路的药物进行评估，目的是确定和实施一些药物，这些药物可能会对正常组织提供选择性的辐射保护，可能会使肿瘤增敏。该项目的另一个主要目标是开发功能成像技术，以更好地表征在肿瘤微环境和正常组织中可能防止或减少试剂影响辐射反应的重要因素。众所周知，低氧是辐射敏感性的主要决定因素，许多人类肿瘤是低氧的。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，以便患者的肿瘤治疗方案可以根据个人情况进行优化。我们已经证明，锂酞菁晶体在组织中的放置提供了一种通过电子顺磁共振(EPR)评估组织氧水平的准确方法。利用放射生物学分部开发的新型EPR设备，我们最近已经证明，可以使用特定的氧化还原探针造影剂来评估小鼠体内的非侵入性组织氧浓度。在氧分辨率为0.5 mm的情况下，在不到3分钟的时间内就可以获得氧的三维图像。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. 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.