Realizing the radiobiological impact of protons and high-LET particles in head and neck cancer and glioblastoma models

认识质子和高 LET 粒子对头颈癌和胶质母细胞瘤模型的放射生物学影响

• 批准号: 10441141
• 负责人: Jason Parsons
• 金额: $ 32.87万
• 依托单位: UNIVERSITY OF LIVERPOOL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-01-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10441141
• 关键词: 3-Dimensional; Acute; Automobile Driving; Biologic Characteristic; Biological; Biological Process; Biology; Brain; Brain Neoplasms; Cell Survival; Cell model; Cells; Characteristics; Chronic; Clinical Oncology; Complex; DNA; DNA Damage; DNA Double Strand Break; DNA Repair; Data; Deposition; Development; Distal; Dose-Rate; Drug Targeting; Electron Transport; Frequencies; Future; Glioblastoma; Head and Neck Cancer; Head and Neck Neoplasms; Helium; High-LET Radiation; Human; Hypoxia; Ions; Knowledge; Lead; Linear Energy Transfer; Malignant Neoplasms; Mediating; Modeling; Molecular; Normal Cell; Normal tissue morphology; Organ; Oxygen; Patients; Pharmaceutical Preparations; Photons; Protons; Radiation; Radiation Dose Unit; Radiation Physics; Radiation Tolerance; Radiation therapy; Radiobiology; Relative Biological Effectiveness; Research; Resistance; Resources; Risk; Role; Sampling; Solid; Solid Neoplasm; Techniques; Therapeutic; Therapeutic Effect; Time; Tissues; Tumor Tissue; Uncertainty; X-Ray Medical Imaging; cancer therapy; cell killing; cellular targeting; combinatorial; comparative; effective therapy; improved; inhibitor; interest; irradiation; neoplastic cell; novel; optimal treatments; particle; patient response; proton beam; radiation effect; radiation resistance; radioresistant; response; screening; side effect; three-dimensional modeling; treatment strategy; tumor; two-dimensional

Project Summary Radiotherapy is still one of the most effective cancer treatments used to treatment ~50 % of all human cancers, and particularly solid tumours of the head and neck and brain. However, acute and long term adverse side effects of radiotherapy are still common, and some tumours are also resistant to the therapeutic effects of the radiation. The increased use of precision particle radiotherapy, particularly proton beam therapy, enables the radiation dose to be delivered precisely to the tumour, which spares the surrounding normal tissues of any unwanted radiation dose and is therefore able to limit some of the adverse side effects. Furthermore, the ability to deliver radiation that causes extensive damage to the tumour tissues (so called “high-LET”) is also a significant advantage in effective radiotherapy. However despite this, there is still uncertainty regarding the biological effects of protons and high-LET radiation on both normal and tumour cells and tissues, and how the radiotherapy can be optimised for patient benefit. This proposal brings together world leading experts in radiation physics, biology and clinical oncology to reveal new knowledge of the biological impact of protons and high-LET radiation versus conventional (x- ray) radiotherapy, on cell models of head and neck and brain tumours. This will be performed on both 2- dimensional, but also 3-dimensional cell models of the tumours which are more similar to those observed in patients. We will thoroughly analyse the precise effect of protons and high-LET radiation at the molecular (DNA) level, and how this correlates with the impact on overall survival of the cells. We will also investigate the role of important factors such as low oxygen levels (hypoxia) which is important in driving resistance of solid tumours of the head and neck and brain to radiotherapy, but also the rate at which the radiotherapy is delivered (particularly high dose rates, so called “FLASH”), on the biology and survival of the tumour versus the normal cells. Additionally, we will identify the combination of specific drugs and inhibitors under the various conditions that are more effective in combination with protons and high-LET radiation in optimising tumour cell killing, whilst sparing the associated normal cells. In the long term, our research will contribute to the identification and development of more effective strategies using radiotherapy, including proton beam therapy, for tumours of the head and neck and brain that are particularly resistant to the radiation treatment. This will lead to an improvement in the patient response but also in overall survival following precision particle radiotherapy. 1

项目摘要 放射治疗仍然是最有效的癌症治疗方法之一，用于治疗约50%的人类癌症。 癌症，特别是头颈部和脑部的实体瘤。然而，急性和长期 放射治疗的副作用仍然很常见，有些肿瘤对放射治疗也有抵抗力。 辐射的治疗效果。增加使用精确粒子放射治疗，特别是质子 射束治疗，使辐射剂量被精确地输送到肿瘤，这节省了 周围正常组织的任何不需要的辐射剂量，并因此能够限制一些 不良副作用此外，提供对组织造成广泛损伤的辐射的能力也是不可能的。 肿瘤组织（所谓的“高LET”）在有效的放射治疗中也是显著的优点。然而 尽管如此，关于质子和高LET辐射对生物的影响，仍然存在着不确定性。 正常和肿瘤细胞和组织，以及如何优化放射治疗以使患者受益。 该提案汇集了世界领先的辐射物理学、生物学和临床肿瘤学专家， 揭示了质子和高LET辐射与常规（X-射线）相比的生物影响的新知识。 射线）放射治疗，在头颈部和脑肿瘤的细胞模型上。这将在2- 三维的，而且三维的肿瘤细胞模型，更类似于那些观察到的 在病人身上。我们将彻底分析质子和高LET辐射在分子中的精确作用， (DNA)水平，以及这与细胞总体存活的影响如何相关。我们亦会研究 重要因素的作用，如低氧水平（缺氧），这是重要的驱动阻力， 头部、颈部和大脑的实体瘤接受放射治疗的比率，而且放射治疗的 递送（特别是高剂量率，所谓的“FLASH”）对肿瘤的生物学和存活率的影响， 正常的细胞。此外，我们还将在以下条件下确定特定药物和抑制剂的组合： 各种条件，更有效地结合质子和高LET辐射，在优化 杀死肿瘤细胞，同时保留相关的正常细胞。 从长远来看，我们的研究将有助于识别和开发更有效的 使用放射疗法，包括质子束疗法治疗头颈部和脑部肿瘤的战略 对放射治疗有很强的抵抗力这将导致患者的改善 精确粒子放射治疗后的总体生存率也有所提高。 1