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

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，特别是头部、颈部和大脑的实体肿瘤。然而，急性和长期的 放射治疗的副作用仍然很常见，一些肿瘤也对 放射治疗的效果。精密粒子放射治疗，特别是质子放射治疗的使用增加 射线治疗，使辐射剂量能够准确地传递到肿瘤，这节省了 正常组织周围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，辐射对人体造成广泛损害的能力 肿瘤组织(所谓的高LET)也是有效放射治疗的一个显著优势。然而， 尽管如此，关于质子和高LET辐射的生物效应仍然存在不确定性。 包括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。 这项建议汇集了辐射物理、生物学和临床肿瘤学方面的世界领先专家，以 揭示质子和高LET辐射与常规(x-2)辐射的生物影响的新知识 射线)放射治疗，用于头颈部和脑肿瘤的细胞模型。这将在以下两个服务器上执行： 更接近于观察到的肿瘤的三维细胞模型 在病人身上。我们将深入分析质子和高LET辐射对分子的精确影响 (DNA)水平，以及这与对细胞总体存活的影响有何关联。我们还将调查 重要因素的作用，如低氧水平(低氧)，这是驱动阻力的重要因素 对头颈部和脑部实体瘤的放疗，还要看放疗的速度 提供(特别是高剂量率，所谓的“闪光”)，对肿瘤的生物学和存活率与 正常细胞。此外，我们将根据 在与质子和高LET辐射相结合时更有效的各种条件 肿瘤细胞被杀死，而相关的正常细胞则幸免于难。 从长远来看，我们的研究将有助于识别和开发更有效的 头颈部和脑部肿瘤的放射治疗策略，包括质子治疗 对放射治疗特别有抵抗力。这将使病人的病情好转。 精确粒子放射治疗后的疗效和总存活率也是如此。 1

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