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.

项目概要/摘要 非小细胞肺癌（NSCLC）是美国最常见的癌症死亡原因之一，尽管 尽管最近取得了进展，但总体 5 年生存率仍然很低（约 20%），迫切需要开发新的药物。 目前的研究小组最近提出了提高生存率和保持生活质量的无毒方法。 做出了令人兴奋和意想不到的发现，独特的非电离正交电磁场（EMF） 显着降低 A549 和 H1299 NSCLC 细胞系中的克隆存活率 此外，在 A549 中。 异种移植模型中，EMF 治疗联合治疗可显着减缓肿瘤生长并提高总体生存率 与传统的放化疗相比，并且耐受性良好，没有明显的不良反应。 暗示性的，磷酸化的 H2AX（DNA 损伤的标记物）在 EMF 处理中也显着升高 肿瘤，表明氧化 DNA 损伤增加。这些初步发现表明 EMF 可能会增加。 作为联合疗法癌症治疗的有效佐剂，现在迫切需要确定。 与这种新方法相关的可行性和具体机制。 建议的目的是确定正交应用 EMF 可以提供安全且可靠的具体机制。 根据初步数据，我们在临床前小鼠模型中作为放化疗的有效辅助剂。 提升正交定向 EMF 选择性地提高 O2●- 和 H2O2 的稳态水平 癌细胞导致代谢氧化应激、DNA 损伤和放射化学敏感性 两个。 具体目标将解决该假设，包括： 目标 1. 确定 EMF 治疗结果的程度 O2●- 和 H2O2 驱动的癌细胞特异性氧化应激导致 DNA 损伤和反应增强 体外放化疗；目标 2. 确定安全性和有效性以及 O2●- 的参与 和 H2O2 在 EMF 增强异种移植体内癌症治疗反应的机制中 和使用强力霉素诱导的非小细胞肺癌原位小鼠模型。 将利用抗氧化酶和生化参数来指示氧化应激的测量 如果成功，该提案将直接涉及 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相关的新颖探索性研究 开发基于电磁场的新型癌症疗法，这可能会导致首次人体临床试验的成功。 这项工作的完成还将严格定义癌细胞特异性 EMF 效应的作用机制 O2●-和H2O2介导的代谢氧化应激这些数据可用于支持临床。 开发一种非侵入性、无毒的基于 EMF 的组合方法，适合早期阶段 NSCLC 人类受试者的临床试验。