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

基本信息

批准号：
10559547
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
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-08 至 2025-01-31
项目状态：
未结题

项目摘要

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）的关键且在很大程度上没有研究的角色通过用去甲肾上腺素驱动的激活来调节放射治疗（RT）的总体效率（RT） β-肾上腺素受体。我们的初步数据表明，肾上腺应力信号传导钝了通过至少两种途径进行辐照的肿瘤：a）抗肿瘤免疫反应的损害，限制辐射控制非辐射远处肿瘤（脱型肿瘤）在体内和b）增加的能力肿瘤细胞对体外辐射的固有阻力。这些数据支持令人兴奋的假设简单而新颖的策略，将RT与β-肾上腺素能受体（β-AR）拮抗剂（即β受体阻滞剂）相结合显着，安全地增强了肿瘤细胞对放射治疗的敏感性并刺激抗肿瘤免疫。我们选择通过采用一种创新的方法来检验这一假设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，压力生物学和肿瘤免疫学方面的免费专业知识将合作，以优化前临床方案与β受体阻滞剂结合并识别基础细胞和分子的关键机制。目的是：目标1：检验以下假设：辐射的总体反应通过β-ARS信号传导调节辐照的肿瘤和远处的非辐照肿瘤）。我们将使用不同小鼠菌株和不同辐射的几种不同且与临床相关的肿瘤模型协议，定义辐射效率对β-AR信号传导的依赖性。重要的是，我们有价值 β-AR敲除小鼠有助于查明宿主肾上腺素信号的作用。目标2和3将评估间接以及肾上腺应力可以调节辐射效率的直接机制。 AIM 2意志评估免疫学和物理因素在肿瘤微环境中的作用，包括分析辐射和免疫疗法与抗PD-1的组合如何受到β-的添加的影响阻滞剂。 AIM 3将评估肾上腺应激信号传导是否可以直接影响肿瘤的灵敏度细胞通过改变抗凋亡分子的平衡或是否改变了辐射和细胞毒性细胞涉及控制肿瘤细胞对杀伤的敏感性的其他途径。我们团队之间持续不断的实时信息应导致优化协议，以增强信心我们对肾上腺素信号封锁对放射治疗的影响的影响是预测患者的反应。使用不同的模型和RT进行同时进行实验两个不同中心的协议将使我们能够测试更多的肿瘤模型，并提高严格，透明度和我们总体结论的可重复性。总体而言，这将产生强大的数据以促进在两个中心的大型随机研究设计。