Project 3: Carbon and Electron FLASH radiotherapy for mitigation of normal lung injury in NSCLC

项目3：碳和电子闪光放射治疗减轻非小细胞肺癌的正常肺损伤

• 批准号: 10573292
• 负责人: Amir Abdollahi
• 金额: $ 38.75万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-15 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10573292
• 关键词: 3-Dimensional; Affect; Biophysics; Blood Vessels; Cancer Etiology; Cancer Model; Cancer Patient; Carbon; Carbon ion; Cardiovascular system; Cells; Cessation of life; Chest; Chronic Obstructive Pulmonary Disease; Data; Dependence; Development; Distant Metastasis; Dose; Dose Rate; Electrons; Endostatins; Esophagus; Evolution; Exposure to; Fiber Optics; Foundations; Functional disorder; Gender; Genes; Goals; Heart; Heavy Ions; Heterogeneity; Homeostasis; Human; Hypoxia; Immune response; In Vitro; Inferior; Inflammatory Response; Inter-tumoral heterogeneity; Interferon Activation; Interferons; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of thorax; Memory; Modality; Modeling; Molecular; Monitor; Non-Small-Cell Lung Carcinoma; Normal tissue morphology; Organ; Organoids; Outcome; Oxygen; Pathway interactions; Perfusion; Phenotype; Physiological; Population; Pre-Clinical Model; Probability; Protons; Pulmonary Fibrosis; Quality of life; Radiation; Radiation Dose Unit; Radiation Tolerance; Radiation Toxicity; Radiation therapy; Regimen; Resistance; Resolution; Risk; Role; Signal Transduction; Site; Solid; Stimulator of Interferon Genes; Structure of parenchyma of lung; Testing; Therapeutic; Tissues; Toxic effect; Transforming Growth Factor beta; Tumor Oxygenation; clinical translation; clinically significant; comorbidity; connective tissue growth factor; curative treatments; fibrotic lung; genetic regulatory protein; image guided; immune checkpoint blockade; in vivo; in vivo monitoring; innovation; insight; irradiation; lung injury; multiscale data; new technology; novel; optical fiber; optical sensor; particle; pressure; primary endpoint; protective effect; rapid detection; regeneration potential; senescence; sensor; tissue injury; tool; transcriptomics; translational study; tumor; tumor growth; tumor hypoxia

Summary Project 3 Late toxicity of thoracic irradiation limits curative treatment of lung cancer and compromises long-term life quality. Radiation induced lung fibrosis (RILF) is among the paradigm organs at risk (OAR) models for which evidence for substantial reduction in late toxicity of electron FLASH irradiation was successfully demonstrated. Moreover, the physiological oxygen condition has been postulated to govern the FLASH protective effect in normal tissues while relatively hypoxic tumors demonstrate similar level of sensitivity. The only possibility to provide ultra-high dose rate FLASH irradiation for deep-seated thoracic malignancies will be to utilize particles. Therefore, this project aims to provide evidence if Carbon-, Proton- and Electron FLASH will spare OAR (lung, vascular, heart and esophagus) following thoracic irradiation from early/late toxicities while demonstrating non-inferiority in terms of local control of non-small cell lung cancer (NSCLC) tumors. Whole thoracic irradiation (WTI) and focal irradiation are performed with carbon ions, protons and electron (reference particle) FLASH vs. S-PRT. The impact of FLASH on lung microvascular damage and M2 polarized inflammatory response in fibrotic lung tissue as well as in-field heart- and GI-toxicity (esophagus) will be examined. Reduced oxygen dependence of high- LET carbon ion FLASH could be further instrumental in exploration of the impact of transient hypoxia for the emergence of FLASH effect. In addition to LET modulation with carbon ions, further development of an ultra- rapid optical sensor for O2 is envisioned to online monitor, prove or disprove the postulated oxygen dependence of FLASH effect in-vitro and in-vivo. Based on increasing application of salvage reirradiation of thoracic malignancies, the impact of FLASH in sparing OAR toxicity post exposure to initial fractionated WTI will be studied and surrogates of tissue radiation memory, i.e. molecular as well as senescent-cells like phenotypic switches will be deconvoluted at single cell resolution. Considering potential differences in pathophysiology of FLASH, the relevance of TGFbeta, CTGF and endostatin as key players of RILF in mitigating FLASH effects will be evaluated. In context of tumor control, the consequence of intratumoral oxygenation heterogeneity on FLASH effect will be studied. Assuming that in analogy to normal tissue, well perfused tumor regions may be spared by FLASH, demonstration of non-inferiority of F- vs. S-PRT in tumor growth inhibition will be of utmost significance for clinical translation of FLASH. In addition to OER effect, implication of intertumoral heterogeneity on F-PRT efficacy will be elucidated by studying relevant pathways involved in ROS homeostasis rendering tumor resistant to S-RT in NSCLC patients. The relevance of LET and partial oxygen pressure on FLASH effect will be further systematically studied in 3D in-vitro tumor models and microvascular organoids. Based on preliminary data that interferon signaling might be differentially affected by FLASH, the cascade of cytosolic cGas/STING/IFN activation is examined and its potential consequence for inferior outcome in combination strategies with immune- check-point blockade, as recently approved standard regimen for NSCLC, will be evaluated.

摘要项目3 胸腔辐照的晚期毒性限制了对肺癌的治疗治疗，并损害了长期的生命质量。 辐射诱导的肺纤维化（RILF）是有风险的范式（OAR）模型之一 为了大大降低电子闪光照射的晚期毒性。而且， 已经假定生理氧气状况是为了控制正常组织的闪光保护作用 而相对缺氧的肿瘤表现出相似的敏感性水平。提供超高的唯一可能性 深层胸腔恶性肿瘤的剂量速率闪光照射将是利用颗粒。因此，这个 项目旨在提供证据，如果碳，质子和电子闪光灯可以备桨（肺，血管，心脏） 和食道）在早期/晚期毒性中进行胸腔照射后，同时证明了不劣效率 非小细胞肺癌（NSCLC）肿瘤的局部控制。整个胸腔辐照（WTI） 和焦点 辐照是 用碳离子，质子和电子（参考粒子）闪光与S-prt进行。这 闪光灯对纤维化肺组织中肺微血管损伤和M2极化反应的影响 还将检查以及野外心脏和胃肠道（食管）。高氧依赖性降低 让碳离子闪光可能进一步探索瞬时缺氧对 闪光效应的出现。除了让碳离子调制，进一步发展了 O2的快速光学传感器设想在线监视器，证明或反驳假定的 氧依赖性 闪光灯 效应体内和体内。基于增加的挽救胸腔启示的应用 恶性肿瘤，在暴露于初始分数WTI后，闪光的影响在保留OAR毒性中的影响将是 组织辐射记忆的研究和替代物，即分子和衰老细胞，例如表型 开关将在单细胞分辨率下进行反驳。考虑到潜在的病理生理学差异 Flash，TGFBETA，CTGF和Endostatin作为RILF的关键参与者的相关性将在减轻闪光效果中 进行评估。在肿瘤控制的背景下，闪光灯内肿瘤内氧合异质性的结果 效果将被研究。假设以与正常组织类似，灌注良好的肿瘤区域可以通过 Flash，在肿瘤生长抑制中F-S-PRT的不效率的证明将是最重要的 用于闪光的临床翻译。除了OER效应之外，对F-PRT的肿瘤间异质性的影响 通过研究相关途径，将阐明功效 参与ROS稳态 抗肿瘤 NSCLC患者的S-RT。 LET和部分氧对闪光效应的相关性将进一步 在3D体外肿瘤模型和微血管类器官中进行了系统的研究。基于初步数据 干扰素信号可能是 受到差异影响 闪光灯，胞质CGA/sting/ifn的级联 检查了激活及其对免疫组合策略中劣质结果的潜在影响 - 将评估NSCLC的最近批准的标准方案的检查点封锁。