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 放射疗法仍然是用于治疗约50％人类的最有效的癌症治疗方法之一 癌症，尤其是头部，颈部和大脑的实体瘤。但是，急性和长期 放疗的不良副作用仍然很常见，有些肿瘤也对 辐射的治疗作用。精确粒子放疗的使用增加，尤其是质子 光束治疗，使辐射剂量能够精确地递送到肿瘤，这使肿瘤宽恕了 围绕任何不需要的辐射剂量的正常时间，因此能够限制一些 不良副作用。此外，传递辐射的能力会造成广泛损害的辐射 在有效放射疗法中，肿瘤组织（所谓的“高LET”）也是一个重要的优势。然而 尽管如此，关于质子的生物学效应和高质LET辐射对 正常和肿瘤细胞和组织，以及如何优化放射疗法以使患者受益。 该建议将辐射物理学，生物学和临床肿瘤学领域的世界领先专家汇集到 揭示了有关质子和高质LET辐射与常规的生物学影响的新知识（X- 射线放疗，在头部和颈部和脑肿瘤的细胞模型上。这将在两个2-上进行 肿瘤的维度，但也与观察到的3维细胞模型更相似 在患者中。我们将彻底分析质子在分子处的精确效应 （DNA）水平，以及这与对细胞总体存活的影响如何相关。我们还将调查 重要因素的作用，例如低氧水平（缺氧），这对于驱动阻力的重要性很重要 头部，颈部和大脑的实体瘤进行放射疗法，但放射疗法的速率也为 在肿瘤的生物学和生存与肿瘤的生物学和生存中，交付的（部分高剂量率） 正常细胞。此外，我们将确定特定药物和抑制剂的组合 各种条件更有效地与质子结合使用，并在优化的高质量辐射中 肿瘤细胞杀死，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发展更有效的 使用放射疗法（包括质子束疗法）的策略 对辐射治疗的抗药性尤其耐药。这将导致患者的改善 反应，但在精确颗粒放疗后的总生存期。 1