Impact of Host NF-kB Signaling in Radiation Therapy

宿主 NF-kB 信号传导在放射治疗中的影响

基本信息

批准号：
10434953
负责人：
SHIGEKI MIYAMOTO
金额：
$ 36.89万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10434953
关键词：
Animals Antitumor Response Arginine Attenuated CD8-Positive T-Lymphocytes Cancer Patient Cell Surface Receptors Cells Cessation of life Chemicals Chronic Clinical Clinical Trials Clonal Expansion DNA Binding DNA Damage Data Defect Dose Drug usage Family Generations Genes Immune Inflammatory Response Investigation Ionizing radiation Irradiated tumor Knowledge Lead Lysine Mediating Memory Molecular Mus Mutagens Mutate NF-kappa B Nuclear Oxidative Stress Pathway interactions Phase I Clinical Trials Phase II Clinical Trials Physiological Post-Translational Protein Processing Publications Radiation Radiation therapy Regenerative capacity Research Role Schedule Signal Pathway Signal Transduction T cell response T memory cell Testing Time Translations Transplantation Treatment Efficacy Tumor Antigens Wild Type Mouse anti-PD-1 base cancer cell cell killing checkpoint therapy improved in vivo inhibitor innovation irradiation mouse model mutant neoplastic cell novel novel therapeutics patient safety response stem-like cell stemness success transcription factor tumor tumorigenesis

项目摘要

PROJECT SUMMARY / ABSTRACT Investigation of cytoplasmic-to-nuclear (C→N) NF-κB signaling pathways induced by various cell surface receptors has significantly expanded the knowledge regarding the role of this transcription factor family in regulating immune/inflammatory responses and tumorigenesis. By contrast, the physiological role of DNA damage-induced nuclear-to-cytoplasmic (N→C) NF-κB signaling remains poorly understood. The proposed study will fill this knowledge gap by elucidating a surprising and crucial role of N→C NF-κB signaling in sustaining anti-tumor CD8 T cell responses during radiotherapy (RT) in vivo. The current proposal utilizes a genetically modified mouse model that selectively disables N→C NF-κB signaling in vivo. Our preliminary data show that radiation therapy can induce sustained regression of syngeneic tumors in a manner dependent on CD8 T cells. We also found that a special type of memory CD8 T cells implicated in tumor control is expanded in this mouse model. Finally, we have generated an encouraging data with an NF-kB DNA binding inhibitor to induce sustained tumor regression following radiation therapy. Based on these observations, we hypothesize that inhibition of N→C NF-κB signaling in the host improve radiation therapy via generation of tumor antigen-specific memory CD8 T cells. We will test this hypothesis by define the cellular mechanism of sustained tumor control mediated by inhibiting host N→C NF-κB signaling in radiation therapy (Aim 1), elucidate the molecular mechanism of sustained tumor control mediated by inhibiting host N→C NF-κB signaling in radiation therapy (Aim 2) and target host N→C NF-κB signaling with a chemical inhibitor to improve radiation therapy (Aim 3). The proposed study is significant because the physiological role of N→C NF-κB signaling in modulating host tumor response is completely undefined and this study will fill this knowledge gap. It is innovative because a new mouse model and a novel chemical inhibitor currently undergoing Phase 2 clinical trials will be employed. Finally, a high impact is expected because chemical targeting of N→C NF-κB signaling by the above inhibitor may expedite timely translation to clinical trials.

项目摘要 /摘要细胞质至核（C→N）NF-κB信号传导途径的研究接收者大大扩展了有关该转录因子家族作用的知识调节免疫/炎症反应和肿瘤发生。相比之下，DNA的身体作用损伤引起的核能质质（N→C）NF-κB信号传导仍然了解不足。提议研究将通过阐明N→C NF-κB信号在维持中的惊喜和关键作用来填补这一知识差距放疗期间（RT）在体内的抗肿瘤CD8 T细胞反应。当前的提案利用一般修饰的小鼠模型在体内有选择地禁用N→C NF-κB信号传导。我们的初步数据表明放射疗法可以以依赖CD8 T细胞的方式诱导合成肿瘤的持续消退。我们还发现，在肿瘤控制中实现的一种特殊类型的内存CD8 T细胞在此鼠标中扩展模型。最后，我们用NF-KB DNA结合抑制剂产生了一个令人鼓舞的数据，以诱导持续的数据放射治疗后肿瘤回归。基于这些观察，我们假设抑制 N→宿主中的C NF-κB信号传导通过产生肿瘤特异性记忆来改善辐射疗法 CD8 T细胞。我们将通过定义持续肿瘤控制的细胞机制来检验该假设通过抑制放射治疗中的宿主n→C NF-κB信号传导（AIM 1），阐明了分子机制持续的肿瘤对照在放射治疗中抑制宿主N→C NF-κB信号传导（AIM 2）和靶标介导带有化学抑制剂的宿主N→C NF-κB信号传导改善放射治疗（AIM 3）。拟议的研究是重要的是因为N→C NF-κB信号在调节宿主肿瘤反应中的身体作用是完全不确定，这项研究将填补这一知识差距。这是创新的，因为新的鼠标模型和当前正在进行2期临床试验的新型化学抑制剂将采用。最后，高影响力是由于上述抑制剂对N→C NF-κB信号传导的化学靶向可能会及时加快翻译为临床试验。