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.

项目总结/摘要 非小细胞肺癌（NSCLC）是美国癌症死亡的最常见原因之一，尽管 尽管最近的进展，总体5年生存率仍然很低（~20%）。迫切需要开发新的 无毒的方法来提高生存率和保持生活质量。目前的研究团队最近在 令人兴奋和意想不到的发现，独特的非电离正交电磁场（EMF） 显著降低A549和H1299 NSCLC细胞系的克隆形成存活率。此外，A549 在异种移植模型中，当联合使用时，EMF治疗显著减缓了肿瘤生长并提高了总生存率。 与常规的放射-化学疗法相结合，并且耐受性良好，没有明显的副作用。 有趣的是，磷酸化的H2 AX，DNA损伤的标志物，也显着升高，在EMF处理， 肿瘤，表明氧化DNA损伤增加。这些初步研究结果表明，电磁场可能 作为癌症联合治疗的有效辅助剂。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。当前的总体目标 建议是确定具体的机制，从而正交应用电磁场可以提供一个安全， 在临床前小鼠模型中对放射-化学疗法有效的辅助剂。根据初步数据，我们 假设正交取向电磁场选择性地增强了O2●-和H2 O2的稳态水平， 癌细胞导致代谢氧化应激、DNA损伤和放射-化学-敏化。两 具体目标将阐述假设，包括：目标1。确定电磁场治疗的效果 在O2●-和H2 O2驱动的癌细胞特异性氧化应激中，导致增强的DNA损伤和反应 体外放化治疗;目标2.确定安全性和有效性以及O2的参与●- 和H_2O_2在利用异种移植物的体内肿瘤治疗反应的EMF增强机制中的作用 和NSCLC的原位小鼠模型。使用强力霉素诱导的复杂遗传方法 将利用抗氧化酶和指示氧化应激的生化参数的测量 来验证这个假设如果成功，该提案将直接解决R21计划公告（PAR-20- 292），通过提供与癌症治疗相关的新型探索性研究和创新的临床前研究 开发新的基于电磁场的癌症疗法，这可能导致首次在人体临床试验。成功 这项工作的完成还将严格地确定癌细胞特异性电磁场效应的作用机制 涉及由O2●-和H2 O2介导的代谢氧化应激。这些数据可用于支持临床 开发一种无创、无毒的基于EMF的联合模式方法， 在患有NSCLC的人类受试者中进行的临床试验。