How does the tumour microenvironment affect cancer cell responses to DNA damage repair inhibition during radiotherapy?

我们的研究旨在开发有选择性地利用肿瘤反应的治疗方法，以提高放射治疗的疗效和耐受性。我们感兴趣的是DNA损伤敏感性如何在辐射和不同的肿瘤微环境和代谢背景下被调节。我们的工作与MRC开发精准医学和先进疗法的主题密切相关。DNA损伤反应（DDR）抑制剂是一种很有前景的新型分子药物，它可以抑制肿瘤细胞修复放射和化疗引起的DNA损伤的能力，提高其治疗效果。我们的团队是最早发现DNA聚合酶作为抗癌靶点的团队之一。DNA聚合酶theta在大多数正常组织中低表达，但在许多癌症类型中经常过表达，是理想的肿瘤选择性靶标。我们与我们的商业合作伙伴（Artios）长期合作，测试有效的一流DNA聚合酶抑制剂，目前已进入临床试验阶段。总之，我们最近证明了这些抑制剂在同源重组缺陷肿瘤细胞中引起合成致死。肿瘤细胞的代谢可塑性受微环境变化的影响，并与DNA损伤疗法的耐药性有关，因此是提高治疗效果的关键靶点。肿瘤缺氧使其对许多癌症治疗特别是放射治疗产生耐药性。希金斯小组最近开发出了逆转肿瘤缺氧的化合物，并已进入临床试验阶段。该项目将筛选不同的癌细胞系，以寻找不同肿瘤微环境条件（如缺氧、低血糖等）对DDRi和放射治疗的反应。该项目将从2D模型开始，有可能继续进行3D体外和体内模型。牛津大学将提供在这一领域进行高质量研究的设施，包括缺氧室，专门的辐照设备（如超软x射线和FLASH辐照），以及靶向和非靶向代谢组学的学术合作。Artios Pharma是一家领先的独立DNA损伤反应公司，该公司将为学生提供新型抑制剂进行测试，并提供大学无法提供的培训和技术。这将包括分子DNA修复测定和与DNA修复监测相关的高含量显微镜。牛津大学和阿蒂奥斯大学获得的结果将为DDR抑制剂的疗效、肿瘤微环境和与放射治疗相关的癌症代谢提供新的见解。希望这项工作将有助于设计未来的试验和指导患者分层。该项目将有助于更好地了解不同的肿瘤微环境如何影响癌细胞对DDR抑制剂和放射治疗的反应。这是放射生物学的一个方面，没有得到很好的研究，这个项目的受益者将是DNA修复和癌症代谢领域。我们期望在高影响力的癌症杂志上发表这个项目的结果。大学和学术合作伙伴也将从这种伙伴关系中受益。该大学将从商业合作伙伴那里获得新型DDR抑制剂和技术专长的独特途径。商业合作伙伴将受益于我们的专业知识和模拟微环境条件的设施，先进的辐射技术，以及我们与代谢组学设施的合作。我们预计这将为其化合物在不同生物环境中的行为提供有价值的实验结果。该项目将具有强大的翻译重点，以帮助指导这些化合物的临床试验设计和未来患者的分层。

Our research aims to develop therapies that selectively exploit tumour responses to improve radiotherapy efficacy and tolerability. We are interested in how DNA damage sensitivity can be modulated under radiation and in diverse tumour microenvironments and metabolic backgrounds. Our work is strongly aligned with the MRC's themes of developing precision medicine and advanced therapies. DNA damage response (DDR) inhibitors are promising novel molecular agents that inhibit cancer cell's ability to repair the DNA damage from radio- and chemotherapy, enhancing their therapeutic efficacy. Our group was one of the first to identify DNA Polymerase theta as an anti-cancer target. DNA Polymerase theta has low expression in most normal tissues but is frequently overexpressed in many cancer types, representing an ideal tumour-selective target. We have a long-standing collaboration with our commercial partner (Artios) in testing potent first-in-class DNA Polymerase theta inhibitors which have now progressed to clinical trials. Together, we have recently demonstrated that these inhibitors cause synthetic lethality in homologous recombination deficient tumour cells.The metabolic plasticity of tumour cells is influenced by microenvironmental changes and is implicated in resistance to DNA damaging therapies, and therefore a key target to explore in improving therapeutic efficacy. Tumour hypoxia confers resistance to many cancer treatments particularly radiation therapy. The Higgins group has recently developed compounds to reverse tumour hypoxia which have progressed to clinical trials. This project will screen diverse cancer cell lines for vulnerabilities that arise from different tumour microenvironmental conditions (i.e. hypoxia, low glucose etc.) in response to DDRi and radiation treatments. This project will start with 2D models, with the potential to continue to 3D in vitro and in vivo models. The University of Oxford will provide the facilities to conduct high-quality research in this area, including hypoxia chambers, specialised irradiators (e.g., ultra-soft x-rays and FLASH irradiation), as well as academic collaborations for targeted and untargeted metabolomics. Artios Pharma is a leading independent DNA Damage Response company, who will provide the novel inhibitors for the student to test as well as training and access to techniques unavailable at the university. This will include molecular DNA repair assays and high content microscopy linked to DNA repair monitoring. Together the results obtained at Oxford and Artios will provide new insights on DDR inhibitor efficacy, the tumour microenvironment and cancer metabolism in relation to radiation therapy. It is hoped that this work will help the design of future trials and guide patient stratification.This project will lead to a greater understanding of how different tumour microenvironments affect cancer cell responses to DDR inhibitors and radiation therapy. This is an aspect of radiobiology that is not well studied and the beneficiaries of this project will be the DNA repair and the cancer metabolism fields. We expect to publish the results of this project in a high impact cancer journal. The University and the academic partner will also mutually benefit from this partnership. The University will get unique access to novel DDR inhibitors and technical expertise from the commercial partner. The commercial partner will benefit from our expertise and facilities that simulate the microenvironmental conditions, advanced radiation technology, as well as our collaborations with metabolomics facilities. We anticipate this will provide valuable experimental results on the behaviour of their compounds in different biological settings. This project will have a strong translational focus to help guide the design of clinical trials for these compounds and the stratification of future patients.