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: 10333800
• 负责人: Amir Abdollahi
• 金额: $ 32.67万
• 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/10333800
• 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; Foundations; Functional disorder; Gender; Gene Proteins; Goals; Heart; Heavy Ions; Heterogeneity; Homeostasis; Human; Hypoxia; Immune response; In Vitro; Inferior; Inflammatory Response; Inter-tumoral heterogeneity; 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; 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; base; 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 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.

项目总结3 胸部照射的晚期毒性限制了肺癌的治疗并损害长期生活质量。 辐射诱导肺纤维化 (RILF) 是危及器官 (OAR) 模型的范式之一，有证据表明 已成功证明可大幅降低电子闪光辐射的后期毒性。而且， 假设生理氧条件控制正常组织中的 FLASH 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 胸部深部恶性肿瘤的闪光照射剂量率将利用粒子。因此，这 该项目旨在提供碳、质子和电子闪光是否能够避免 OAR（肺、血管、心脏）的证据。 和食道）在早期/晚期毒性的胸部照射后，同时证明在术语上的非劣效性 非小细胞肺癌（NSCLC）肿瘤的局部控制。全胸照射（WTI） 和焦点 照射范围 使用碳离子、质子和电子（参考粒子）FLASH 与 S-PRT 进行比较。这 FLASH对肺纤维化组织中肺微血管损伤和M2极化炎症反应的影响 还将检查现场心脏和胃肠道毒性（食道）。减少高氧依赖 LET 碳离子 FLASH 可以进一步有助于探索短暂缺氧对 FLASH效果的出现。除了用碳离子进行LET调制外，还进一步开发了超 O2 快速光学传感器预计可在线监测、证明或反驳假设的情况 氧依赖性 闪存 体外和体内效果。基于胸部挽救性再照射应用的增加 对于恶性肿瘤，FLASH 在暴露于初始分馏 WTI 后避免 OAR 毒性方面的影响将是 组织辐射记忆的研究和替代，即分子以及衰老细胞如表型 开关将以单细胞分辨率解卷积。考虑到病理生理学的潜在差异 FLASH，TGFbeta、CTGF 和内皮抑素作为 RILF 在减轻 FLASH 效应中的关键角色的相关性将 进行评估。在肿瘤控制的背景下，肿瘤内氧合异质性对 FLASH 的影响 将研究效果。假设与正常组织类似，灌注良好的肿瘤区域可以免受 FLASH，证明 F- 与 S-PRT 在肿瘤生长抑制方面的非劣效性将具有极其重要的意义 用于 FLASH 的临床翻译。除了 OER 效应外，肿瘤间异质性对 F-PRT 的影响 通过研究相关途径来阐明功效 参与 ROS 稳态 使肿瘤具有抗性 NSCLC 患者接受 S-RT。 LET和氧分压对FLASH效果的相关性将进一步 在 3D 体外肿瘤模型和微血管类器官中进行了系统研究。根据初步数据 干扰素信号传导可能是 受到不同程度的影响 通过 FLASH，胞质 cGas/STING/IFN 级联 检查激活及其与免疫联合策略中较差结果的潜在后果 检查点封锁作为最近批准的非小细胞肺癌标准治疗方案将进行评估。