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：
9893829
负责人：
Michael Yi Bonner
金额：
$ 2.53万
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/9893829
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 Immunocompetence Impairment In Vitro Knock-in Mouse Knowledge Lewis Lung Carcinoma Malignant - descriptor Malignant Neoplasms Melanoma Cell Modeling Mouse Strains Mus Mutant Strains Mice 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 public health relevance response therapy resistant thioredoxin reductase transcription factor tumor tumor growth tumor progression

项目摘要

PROJECT SUMMARY 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.

项目摘要尽管癌症生物学进展，但耐药性是患者和临床医生的主要障碍。许多当前癌症治疗部分通过升高活性氧（ROS）产生，通常导致肿瘤回归，随后肿瘤再次发生和治疗性抗性。以前，Kelkka和同事看在巨噬细胞中巨噬细胞中ROS的小鼠中，蛋白质NOX2的肿瘤进展（Kelkka等，2013）。他们得出的结论是，当ROS时，免疫细胞对转移和肿瘤进展更有效巨噬细胞中的产生受到抑制。另一方面，其他人证明了癌变和我们先天的抗氧化剂系统，例如硫氧还蛋白还原酶（TRXR）系统和谷胱甘肽还原系统（Gorrini等，2013）。随着癌变的进展，细胞产生升高罗斯。肿瘤细胞通过适应性抗氧化剂反应（例如硫氧还蛋白）应对高水平的ROS。还原酶系统。但是，当该系统在肿瘤细胞中受损时，体内肿瘤的进展和转移可能会受到显着抑制（Yoo等，2006）。鉴于这些发现，我们认为肿瘤细胞在某种程度上对当前疗法具有抗性 ROS产生的增加，这1）由于其适应性而不足以促进肿瘤细胞的细胞死亡抗氧化剂反应和2）ROS水平升高会损害有效打击肿瘤细胞的免疫细胞。因此，我们建议有效的抗癌治疗需要一种合并的方法。我们假设患有功能失调抗氧化剂系统的肿瘤细胞将显着回归，并且宿主的免疫在低ROS条件下的反应将被启动以放射剩余的恶性肿瘤。该提出的博士学位项目的重点是研究这一假设并表征最佳氧化还原肿瘤回归的条件。我们计划使用两个公认的鼠肿瘤模型来实现这一目标：1）转移性B16F10黑色素瘤和2）转移性刘易斯肺癌，LLC1。我们将以描述在这些肿瘤模型中，体外使用基线氧化还原系统，使用siRNA或CRISPR进行改变。我们也会查看活宿主中的肿瘤进展。我们将使用六种鼠标菌株来帮助我们了解宿主氧化还原生物学，在免疫细胞和系统上响应癌症。具体来说，我们将使用具有关键表型的鼠标模型：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 有条件的敲入小鼠。最后，我们将研究肿瘤氧化还原系统，该系统面临着Auranofin和其他 TRXR1抑制剂。