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

项目概要 放射疗法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，特别是头颈和脑部的实体瘤。然而，急性和长期 放疗的不良副作用仍然很常见，并且一些肿瘤还对放疗产生耐药性。 辐射的治疗效果。精密粒子放射治疗，特别是质子治疗的使用增加 放射治疗，使放射剂量能够精确地传递到肿瘤，从而避免 周围正常组织的任何不需要的辐射剂量，因此能够限制一些 不良副作用。此外，发射辐射的能力会对身体造成广泛损害。 肿瘤组织（所谓的“高LET”）也是有效放射治疗的显着优势。然而 尽管如此，质子和高 LET 辐射对人体的生物效应仍然存在不确定性。 正常细胞和肿瘤细胞和组织，以及如何优化放射治疗以造福患者。 该提案汇集了放射物理、生物学和临床肿瘤学领域的世界领先专家 揭示了质子和高 LET 辐射与传统（x- 射线）放射治疗，用于头颈肿瘤和脑肿瘤的细胞模型。这将在 2- 肿瘤的三维细胞模型，以及与观察到的更相似的 3 维细胞模型 在患者中。我们将彻底分析质子和高 LET 辐射对分子的精确影响 （DNA）水平，以及它与细胞整体存活的影响如何相关。我们也会调查 重要因素的作用，例如低氧水平（缺氧），这对于驱动抵抗力很重要 头颈和脑部实体瘤的放射治疗，以及放射治疗的速率 交付（特别是高剂量率，所谓的“FLASH”），对肿瘤的生物学和存活率 正常细胞。此外，我们将确定特定药物和抑制剂的组合 与质子和高 LET 辐射相结合更有效的各种条件优化 杀死肿瘤细胞，同时不伤害相关的正常细胞。 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）治疗头颈和脑部肿瘤的策略 对放射治疗特别有抵抗力。这将导致患者的病情得到改善 反应以及精密粒子放射治疗后的总体生存率。 1