Targeting adrenergic stress pathways to Increase tumor sensitivity to radiation and promote development of an anti-tumor immune response

针对肾上腺素能应激途径，提高肿瘤对辐射的敏感性并促进抗肿瘤免疫反应的发展

• 批准号: 10331775
• 负责人: Scott Andrew Gerber
• 金额: $ 54.93万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-08 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10331775
• 关键词: Abscopal effect; Adrenergic Agents; Adrenergic Antagonists; Animal Model; Apoptotic; Autonomic nervous system; Biological Assay; Biology; Cancer Patient; Cell Death; Cessation of life; Clinic; Clinical; Clinical Data; Clinical Protocols; Combined Modality Therapy; Comprehensive Cancer Center; Data; Dependence; Development; Distant; Dose; Equilibrium; Growth; Human; Hypoxia; Immune; Immune checkpoint inhibitor; Immune response; Immunologics; Immunosuppression; Immunotherapy; Impairment; In Vitro; Ionizing radiation; Irradiated tumor; Knockout Mice; Laboratories; Link; Malignant Neoplasms; Mediating; Medical center; Methods; Modeling; Molecular; Mouse Strains; Mus; Natural Killer Cells; Neoplasm Metastasis; Nerve; Neurotransmitters; Norepinephrine; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Physiological; Protocols documentation; Publishing; Radiation; Radiation Tolerance; Radiation therapy; Randomized; Receptor Signaling; Reproducibility; Research; Research Personnel; Research Proposals; Resistance; Role; Safety; Shapes; Signal Transduction; Stress; Sympathetic Nervous System; Testing; Time; Tumor Immunity; Tumor Promotion; Universities; adrenergic stress; angiogenesis; anti-PD-1; anti-tumor immune response; base; beta-adrenergic receptor; cancer therapy; cell killing; clinically relevant; clinically significant; cost effective; design; experience; experimental study; improved; in vivo; innovation; neoplastic cell; neurogenesis; novel; novel strategies; patient response; pre-clinical; radiation effect; radiation response; receptor; response; stress reduction; tumor; tumor growth; tumor immunology; tumor microenvironment; tumor progression

Our data reveal a critical and largely unstudied role for the sympathetic nervous system (SNS) in regulating the overall efficacy of radiation therapy (RT), by signaling through norepinephrine-driven activation of β-adrenergic receptors. Our preliminary data reveal that adrenergic stress signaling blunts the response of the irradiated tumor to RT through at least two pathways: a) Impairment of the anti-tumor immune response, limiting the ability of radiation to control non-irradiated distant tumors (abscopal effect) in vivo and b) increasing intrinsic resistance of tumor cells to radiation in vitro. These data support the exciting hypothesis that a simple and novel strategy, combining RT with β-adrenergic receptor (β-AR) antagonists (i.e., β-blockers) significantly and safely enhances the sensitivity of tumor cells to radiation therapy and stimulates anti-tumor immunity. We have chosen to test this hypothesis by taking an innovative approach in which two separate teams, at Roswell Park Comprehensive Cancer Center and University of Rochester Medical Center, with complimentary expertise in radiation, stress biology, and tumor immunology will collaborate to optimize pre- clinical protocols combining RT with β-blockers and to identify key underlying cellular and molecular mechanisms. The aims are: Aim 1: Test the hypothesis that the overall response to radiation (in both primary irradiated tumors and distant, non-irradiated tumors) is regulated by signaling through β-ARs. We will use several different and clinically relevant tumor models in different strains of mice and different radiation protocols, to define the dependence of radiation efficacy on β-AR signaling. Importantly, we have valuable β-AR knockout mice to help pinpoint the role of host adrenergic signaling. Aims 2 and 3 will evaluate indirect and direct mechanisms by which adrenergic stress could be regulating the efficacy of radiation. Aim 2 will evaluate the role of immunological and physiological factors in the tumor microenvironment, including analysis of how combinations of radiation and immunotherapy with anti-PD-1, are influenced by the addition of β- blockers. Aim 3 will evaluate whether adrenergic stress signaling can directly influence the sensitivity of tumor cells to radiation and cytotoxic cells by altering the balance of pro-and anti-apoptotic molecules or whether other pathways that govern tumor cell sensitivity to killing are involved. A constant flow of real-time information between our teams should result in optimized protocols that enhance confidence that our data concerning the impact of blockade of adrenergic signaling on radiation therapy are predictive of patients’ response. Performing simultaneous experiments, using different models and RT protocols in two different centers, will enable us to test more tumor models, and increase rigor, transparency and reproducibility of our overall conclusions. Overall, this will produce the strongest data to facilitate the design of large randomized studies at both centers.

我们的数据揭示了交感神经系统 (SNS) 在 通过去甲肾上腺素驱动的激活信号调节放射治疗 (RT) 的整体疗效 β-肾上腺素能受体。我们的初步数据表明，肾上腺素能应激信号减弱了 受辐射的肿瘤通过至少两种途径进行放疗：a) 抗肿瘤免疫反应受损， 限制辐射在体内控制未辐射远处肿瘤的能力（远隔效应），b) 增加 肿瘤细胞对体外辐射的内在抵抗力。这些数据支持了一个令人兴奋的假设： 简单而新颖的策略，将放疗与 β-肾上腺素能受体 (β-AR) 拮抗剂（即 β-阻滞剂）相结合 显着且安全地增强肿瘤细胞对放射治疗的敏感性并刺激抗肿瘤 免疫。我们选择采用一种创新方法来检验这一假设，其中两个独立的 罗斯威尔公园综合癌症中心和罗切斯特大学医学中心的团队 辐射、应激生物学和肿瘤免疫学方面的互补专业知识将合作优化预治疗 将 RT 与 β 受体阻滞剂相结合的临床方案，并确定关键的潜在细胞和分子 机制。目标是： 目标 1：检验以下假设：对辐射的总体反应（在初级和中级中） 受辐射的肿瘤和远处未受辐射的肿瘤）通过 β-AR 信号进行调节。我们将使用 不同品系小鼠和不同辐射的几种不同且临床相关的肿瘤模型 协议，以确定辐射功效对 β-AR 信号传导的依赖性。重要的是我们有宝贵的 β-AR 敲除小鼠有助于查明宿主肾上腺素信号传导的作用。目标 2 和 3 将评估间接 以及肾上腺素能应激调节辐射功效的直接机制。目标2将 评估免疫和生理因素在肿瘤微环境中的作用，包括分析 放射治疗和抗 PD-1 免疫治疗的组合如何受到添加 β- 的影响 阻滞剂。目标3将评估肾上腺素能应激信号传导是否可以直接影响肿瘤的敏感性 通过改变促凋亡分子和抗凋亡分子的平衡或是否 还涉及控制肿瘤细胞对杀伤敏感性的其他途径。 我们团队之间实时信息的持续流动应该会产生优化的协议，从而增强 我们相信我们关于阻断肾上腺素信号传导对放射治疗的影响的数据是 预测患者的反应。使用不同的模型和 RT 进行同步实验 两个不同中心的协议将使我们能够测试更多肿瘤模型，并提高严谨性和透明度 以及我们总体结论的可重复性。总体而言，这将产生最有力的数据，以促进 两个中心的大型随机研究设计。