Evaluation of Orthogonally Oriented Electromagnetic Fields to Stabilize ROS, Induce DNA damage and Improve Survival in Non-Small Cell Lung Cancer

正交定向电磁场稳定 ROS、诱导 DNA 损伤和提高非小细胞肺癌生存率的评估

• 批准号: 10290446
• 负责人: Val C. Sheffield
• 金额: $ 21.67万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10290446
• 关键词: A549; Address; Adjuvant; Adverse effects; Animals; Biochemical; Biological; Cancer Etiology; Cancer Patient; Cancer cell line; Cell Death; Cellular Metabolic Process; Cessation of life; Chemosensitization; Chronic; Clinical Trials; Coupled; DNA Damage; DNA Markers; DNA Sequence Alteration; Data; Detection; Development; Dose; Doxycycline; Electromagnetic Fields; Electrons; Epithelial Cells; Evaluation; Exploratory/Developmental Grant; Frequencies; Gamma-H2AX; Goals; H1299; Human; Hydrogen Peroxide; In Vitro; Lead; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Measurement; Measures; Mediating; Metabolic; Metabolic Pathway; Modality; NIH Program Announcements; Non-Insulin-Dependent Diabetes Mellitus; Non-Small-Cell Lung Carcinoma; Operative Surgical Procedures; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Publications; Quality of life; Radio; Reactive Oxygen Species; Research; Role; Safety; Superoxide Dismutase; Superoxides; Survival Rate; Techniques; Testing; Therapeutic; Treatment outcome; Work; Xenograft Model; Xenograft procedure; anticancer activity; antioxidant enzyme; base; cancer cell; cancer therapy; catalase; cell killing; chemoradiation; chemotherapy; clinical application; clinical development; combined cancer modality therapy; cytotoxic; early phase clinical trial; electric field; experimental study; first-in-human; follow-up; genetic approach; genetic immunotherapy; glutathione peroxidase; human subject; improved; in vivo; in vivo Model; innovation; insight; lung cancer cell; magnetic field; metabolic abnormality assessment; mouse model; novel; novel strategies; oxidative DNA damage; personalized approach; pre-clinical; preclinical study; preservation; response; tumor; tumor growth

Project Summary / Abstract Non-small cell lung cancer (NSCLC) is one of the most common causes of cancer death in the USA and despite recent advances, the overall 5-year survival rate remains low (~20%). There is an urgent need to develop novel non-toxic approaches to improve survival and preserve quality of life. The current research team has recently made the exciting and unexpected discovery that unique non-ionizing orthogonal electromagnetic fields (EMFs) significantly reduced clonogenic survival in A549 and H1299 NSCLC cell lines. Furthermore, in the A549 xenograft model, EMF treatment significantly slowed tumor growth and improved overall survival when combined with conventional radio-chemo-therapies as well as being well-tolerated with no apparent adverse effects. Interestingly, phosphorylated H2AX, a marker of DNA damage, was also significantly elevated in EMF treated tumors, suggesting an increase in oxidative DNA damage. These preliminary findings suggest that EMFs may serve as an effective adjuvant to combined modality cancer therapies. There is a now critical need to determine the feasibility and specific mechanisms associated with this novel approach. The overall objective of the current proposal is to determine specific mechanisms whereby orthogonally applied EMFs can provide a safe and effective adjuvant to radio-chemo-therapy in preclinical mouse models. Based on preliminary data, we hypothesize that orthogonally oriented EMFs selectively enhance steady-state levels of O2●- and H2O2 in cancer cells leading to metabolic oxidative stress, DNA damage and radio-chemo-sensitization. Two Specific Aims will address the hypothesis including: Aim 1. Determine the extent to which EMF-therapy results in O2●- and H2O2 driven cancer cell specific oxidative stress leading to enhanced DNA damage and responses to radio-chemo-therapy in vitro; and Aim 2. Determine the safety and efficacy as well as the involvement of O2●- and H2O2 in mechanisms responsible for EMF enhancement of cancer therapy responses in vivo using xenograft and orthotopic mouse models of NSCLC. Sophisticated genetic approaches using doxycycline inducible antioxidant enzymes and measurements of biochemical parameters indicative of oxidative stress will be utilized to test the hypothesis. If successful, the proposal directly addresses the R21 program announcement (PAR-20- 292), by providing novel exploratory research relevant to cancer treatment and innovative preclinical studies developing novel EMF-based cancer therapeutics, which could lead to first-in-human clinical trials. Successful completion of this work will also rigorously define mechanisms of action for cancer cell specific EMF effects involving metabolic oxidative stress mediated by O2●- and H2O2. These data can be used to support the clinical development of a non-invasive, non-toxic EMF-based combined modality approaches amenable to early phase clinical trials in human subjects with NSCLC.

项目摘要 /摘要 非小细胞肺癌（NSCLC）是美国癌症死亡最常见的原因之一 最近的进步，总5年生存率仍然很低（约20％）。迫切需要开发小说 提高生存和维护生活质量的无毒方法。当前的研究团队最近有 令人兴奋的意外发现是独特的非离子正交电子场（EMFS） 在A549和H1299 NSCLC细胞系中，克隆生成的生存显着降低。此外，在A549中 异种移植模型，EMF治疗显着减慢了肿瘤的生长，并改善了总体生存率 具有常规的放射性化学处理，并且具有良好的耐受性，没有明显的不利影响。 有趣的是，DNA损伤的标志物磷酸化H2AX在EMF中也显着升高 肿瘤，表明氧化DNA损伤增加。这些初步发现表明EMF可能 作为合并癌症疗法的有效调整。现在有一个迫切需要确定 与这种新方法相关的可行性和特定机制。当前的总体目标 建议是确定正交应用EMF可以提供安全和安全的特定机制 有效调整临床前小鼠模型中的放射性化学疗法。根据初步数据，我们 假设正交的EMF有选择地增强O2的稳态水平● - 和H2O2 癌细胞导致代谢氧化应激，DNA损伤和放射性化学敏感性。二 具体目的将解决该假设，包括：目标1。确定EMF-therapy结果的程度 在O2● - 和H2O2驱动癌细胞特异性氧化应激，导致DNA损伤和反应增强 在体外进行无线电治疗；和目标2。确定O2的安全性和效率以及参与● - H2O2在负责使用异种移植物体内EMF增强癌症治疗反应的机制中 NSCLC的原位小鼠模型。使用强力霉素诱导的精致遗传方法 将利用抗氧化剂酶和生化参数的测量值 检验假设。如果成功，该提案直接解决了R21计划公告（Par-20- 292），通过提供与癌症治疗和创新临床前研究有关的新型探索性研究 开发基于EMF的新型癌症疗法，这可能导致首次人类临床试验。成功的 这项工作的完成还将严格定义针对癌细胞特异性电动势效应的作用机制 涉及由O2介导的代谢氧化应激● - 和H2O2。这些数据可用于支持临床 开发非侵入性的，无毒的基于EMF的联合模态方法可适应早期阶段 NSCLC人类受试者的临床试验。