Radiation-induced molecular targets

我们实验室项目的长期重点涉及辐射和微环境应激反应。我们现在专注于“辐射诱导靶点”，即探索使用多分步（MF）辐射以及更高的单剂量（SD）来诱导细胞表型，使细胞对分子靶向治疗和免疫治疗敏感。从本质上讲，放疗将使肿瘤形成，以增强药物杀伤和增强免疫反应。该项目现已证明，不同剂量的辐射- MF和SD - （10 Gy x1, 2 Gy x5, 1 Gy x10和低至0.5 Gy x10）产生不同的表型。我们已经证明，放射后的细胞在1周和3个月后对放射后的药物比以前更敏感，表明稳定的适应。这适用于可供临床使用的药物。我们现在正在与复杂系统分析方面的专家合作，以确定到达靶点的途径，并研究放射和药物的时机。由于对免疫调节的主要兴趣，我们的工作对可用于肿瘤控制的免疫增强的辐射剂量和分离有重要影响，包括直接和间接效应。我们正在与RBB的吉姆·米切尔和RBB的穆拉利·切鲁库里合作，他拥有超极化磁共振成像技术来研究代谢适应。与这项工作密切相关的是，人们正在努力确定辐射损伤的生物标志物和机制。这与我在卫生与人类服务部（HHS）战略准备和反应管理局（HHS）所做的工作有关。我们正在研究将这些缓解剂引入癌症治疗的潜力。

The long-standing focus of our laboratory program involves the radiation and microenvironmental stress response. We are now focusing on "radiation inducible targets" that is, exploring the use of multi-fractionated (MF) radiation as well as higher single doses (SD) to induce a cellular phenotype that makes the cell susceptible for molecular targeted therapy and immunotherapy. In essence, radiation would set up the tumor for enhanced drug killing and enhanced immune response. This project has now demonstrated that different dose sizes of radiation- MF and SD - (10 Gy x1, 2 Gy x5, 1 Gy x10 and down to 0.5 Gy x 10) produce different phenotypes. We have demonstrated that the cells post-radiation are more drug sensitive to a drug post-radiation than before at 1 week and up to 3 months later, indicating stable adaptation. This is applicable to drugs available for clinical use. We are now working with experts in complex systems analysis to identify pathways to target and working on timing of radiation and drug(s). With the major interest in immune modulation, our work has significant bearing on the dose and fractionation of radiation that can be exploited for immune enhancement for tumor control, including direct and abscopal effects. We are working with Jim Mitchell of RBB and Murali Cherukuri of RBB who has hyperpolarized MRI techniques to study metabolic adaptation. Closely related to this work are efforts being done on identifying biomarkers and machanisms of radiation injury. This relates to work I do in the Administration for Strategic Preparedness and Response in Health and Human Services (HHS). We are working on the potential of bringing these mitigators into cancer care.