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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：
10350881
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 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10350881
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 Lewis lung carcinoma cell 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 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.

项目总结