Redox modulation - Impact on Tumor Growth and Therapeutic Anticancer Efficacy

氧化还原调节 - 对肿瘤生长和抗癌治疗功效的影响

基本信息

批准号：
9563516
负责人：
Michael Yi Bonner
金额：
$ 0.42万
依托单位：
KAROLINSKA INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-01 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9563516
关键词：
Animal Model Antioxidants Auranofin Biology Cancer Biology Cancer Patient Cell Death Cells Clustered Regularly Interspaced Short Palindromic Repeats Detection Doctor of Philosophy Drug resistance Glutathione Reductase Growth Immune Immune response Impairment In Vitro Knock-in Mouse Knowledge Lewis Lung Carcinoma Malignant - descriptor Malignant Neoplasms Melanoma Cell Modeling Mouse Strains Mus NADP NADPH Oxidase NF-kappa B Neoplasm Metastasis Organism Oxidases Oxidation-Reduction Patients Phenotype Plasmids Production Proteins Reactive Oxygen Species Reporter Research Project Grants Resistance Signal Transduction Small Interfering RNA System Testing Therapeutic Work analog anti-cancer therapeutic cancer cell cancer therapy carcinogenesis cell transformation combat improved in vivo in vivo Model inhibitor/antagonist insight macrophage melanoma mouse model neoplastic cell premalignant response therapy resistant thioredoxin reductase transcription factor tumor tumor growth tumor progression

项目摘要

Despite advances in cancer biology, drug resistance is a major obstacle to patients and clinicians. Many current cancer therapeutics work in part by elevating reactive oxygen species (ROS) production, often leading to tumor regression followed by tumor reoccurrence and therapeutic resistance. Previously, Kelkka and coworkers looked at tumor progression in mice with macrophages deficient in ROS from the protein NOX2 (Kelkka et al., 2013). They concluded that immune cells are more efficacious against metastasis and tumor progression when ROS production in macrophages is inhibited. On the other hand, others have demonstrated the relationship between carcinogenesis and our innate antioxidant systems such as the thioredoxin reductase (TrxR) system and the glutathione reductase system (Gorrini et al., 2013). As carcinogenesis progress, cells produce increasing levels of ROS. Tumor cells cope with high levels ROS via an adaptive antioxidant response such as the thioredoxin reductase system. However, when this system is impaired within tumor cells, in vivo tumor progression and metastasis may be significantly inhibited (Yoo et al., 2006). Given these findings, we believe that tumor cells become resistant to current therapies in part by the systemic increase of ROS production, which 1) is insufficient to promote cell death in tumor cells because of their adaptive antioxidant response, and 2) elevated levels of ROS impairs immune cells from effectively combating tumor cells. Therefore we propose that a combined approach is required for effective anticancer therapy. We hypothesize that tumor cells with dysfunctional antioxidant systems will significantly regress and that the host’s immune response, under low ROS conditions, will be primed to eradicate the remaining malignancy. The focus of this proposed PhD project is to investigate this hypothesis and characterize the optimal Redox conditions for tumor regression. We plan to accomplish this using two well-established murine tumor models: 1) the metastatic B16F10 melanoma and 2) the metastatic Lewis Lung Carcinoma, LLC1. We will characterize in vitro the baseline Redox systems in these tumor models, make alterations using siRNA or CRISPR. We will also look at tumor progression in living hosts. We will use six mouse strains to help us understand the significance of host Redox biology, in both the immune cells and systemically, in response to cancer. Specifically, we will use mouse models with key phenotypes: B6.129P2-Txnrd1tm1Marc, B6.129P2-Txnrd1Cond, BQ.Ncf1m1J (Ncf1 mutant mice), BQ.Ncf4 (Ncf4 mutant mice), BQMN (expressing Ncf1 in macrophages only) and BQ.TN3 conditional knock-in mice. Finally, we will study tumor redox systems challenged with Auranofin and other TrxR1 inhibitors.

尽管癌症生物学取得了进展，但耐药性仍然是目前许多患者和信徒的主要障碍。癌症治疗部分通过提高活性氧 (ROS) 的产生来发挥作用，这通常会导致肿瘤此前，Kelkka 和同事曾研究过肿瘤复发和治疗耐药。巨噬细胞缺乏 NOX2 产生的 ROS 的小鼠的肿瘤进展（Kelkka 等，2013）。他们得出的结论是，当 ROS 存在时，免疫细胞能够更有效地对抗转移和肿瘤进展。另一方面，其他人已经证明了巨噬细胞的产生受到抑制。致癌作用和我们先天的抗氧化系统，例如硫氧还蛋白还原酶（TrxR）系统和谷胱甘肽还原酶系统（Gorrini et al., 2013）随着癌变的进展，细胞产生的水平不断增加。肿瘤细胞通过适应性抗氧化反应（例如硫氧还蛋白）应对高水平的 ROS。然而，当肿瘤细胞内该系统受损时，体内肿瘤进展和转移可能会被显着抑制（Yoo et al., 2006）。鉴于这些发现，我们认为肿瘤细胞对当前疗法产生耐药性部分是由于全身系统性的 ROS 产生增加，1）不足以促进肿瘤细胞的细胞死亡，因为它们具有适应性抗氧化反应，2) ROS 水平升高会损害免疫细胞有效对抗肿瘤细胞。因此，我们建议有效的抗癌治疗需要综合方法。抗氧化系统功能失调的肿瘤细胞将显着消退，并且宿主的免疫系统在低活性氧条件下，反应将准备好根除剩余的恶性肿瘤。这个拟议的博士项目的重点是研究这一假设并表征最佳氧化还原我们计划使用两种成熟的小鼠肿瘤模型来实现这一目标：1）转移性 B16F10 黑色素瘤和 2) 转移性 Lewis 肺癌，LLC1。我们还将使用 siRNA 或 CRISPR 对这些肿瘤模型中的基线氧化还原系统进行改变。我们将使用六种小鼠品系来观察活体宿主中的肿瘤进展，以帮助我们了解肿瘤的重要性。具体来说，我们将在免疫细胞和系统中使用宿主氧化还原生物学来应对癌症。具有关键表型的小鼠模型：B6.129P2-Txnrd1tm1Marc、B6.129P2-Txnrd1Cond、BQ.Ncf1m1J（Ncf1 突变体小鼠）、BQ.Ncf4（Ncf4 突变小鼠）、BQMN（仅在巨噬细胞中表达 Ncf1）和 BQ.TN3 最后，我们将研究金诺芬和其他药物攻击的肿瘤氧化还原系统。 TrxR1 抑制剂。