Volatile hypoxia signatures in oesophageal adenocarcinoma

临床需求：在英国，每年有9200名患者被诊断患有食道癌，但100名患者中只有15人有望活过5年。大多数患者对化疗或放射治疗没有反应，这降低了他们的生存机会。迫切需要更有效的治疗方法来改善患者的预后。肿瘤缺氧（“缺氧”）是治疗抵抗的一个原因。有希望的新药已经开发出来，可以减少缺氧，改善患者的预后。然而，先前的研究表明，只有某些患有缺氧肿瘤的患者会有反应。我们目前没有简单的方法来测量肿瘤缺氧（即“生物标志物”），以预测谁将受益或知道药物是否有效。这使得设计临床试验具有挑战性，因此没有低氧靶向治疗被批准用于食管癌。一项测量肿瘤缺氧的简单测试可以加速临床试验，并使这些新药可供患者使用。解决方案：呼吸测试是安全的，患者可以接受的，并且可以很容易地重复。呼吸测试已经在执法中用于检测血液酒精含量，在医疗保健中用于诊断胃部感染（幽门螺杆菌）和哮喘。在伦敦帝国理工学院，我们也证明了使用质谱法测量呼吸中的挥发性化学物质可以准确诊断食道癌。最近的研究表明，其中一些化学物质源于癌细胞，并可能受到缺氧的影响。这可能意味着我们可以通过简单的呼吸测试来测量肿瘤缺氧。目的：本项目旨在开发一种无创呼吸测试方法来预测和监测食管癌患者对低氧靶向治疗的反应。机构：这项研究将通过伦敦帝国理工学院和曼彻斯特癌症研究中心（MCRC）之间的战略合作进行。在过去的两年里，帝国理工学院的挥发性有机化合物（VOC）实验室招募了3000多名消化道癌症患者进行非侵入性诊断的临床试验。MCRC在肿瘤缺氧研究和提供生物标志物驱动的缺氧靶向治疗试验方面拥有丰富的经验。新发现：我们已经确定：(i)可用于检测肿瘤样本缺氧的靶基因（一种缺氧基因“特征”）和（ii）可在呼吸中检测到的肿瘤对缺氧反应产生的挥发性化学物质。项目结构：我们的目标是充分表征由缺氧肿瘤产生的挥发性化学物质及其产生机制。这将涉及分析挥发性化学物质：(i)在相机测试（“内窥镜检查”）中作为常规调查的一部分从患者身上提取的呼吸和癌症组织，以及（ii）在缺氧和正常条件下生长的癌细胞。第二个目标是确定这些化学物质在治疗后的变化。这将涉及分析：(i)在实验室中用低氧靶向药物治疗的细胞，以及（ii）在低氧靶向药物的临床试验中食管癌患者的呼吸。重要性：本项目旨在开发一种无创呼吸测试，以改善患者对靶向缺氧的抗癌药物的选择和监测。这项呼气测试的目的是加速临床试验，为患者提供更有效的治疗方法。治疗监测呼气测试的成功开发也将是全球首例。这种创新的方法可以促进基于呼吸的监测概念在医疗保健领域的广泛应用。

Clinical need: Every year in the UK, 9,200 patients are diagnosed with cancer of the gullet (oesophagus) but only 15 in 100 patients can expect to live beyond five years. Most patients do not respond to chemotherapy or radiation therapy and this lowers their chances of survival. More effective treatments are urgently needed to improve patient outcomes. A lack of oxygen ('hypoxia') in tumours is a cause of treatment resistance. Promising new drugs have been developed which reduce hypoxia and could improve outcomes for patients. However, previous studies have shown that only certain patients with hypoxic tumours will respond. We currently have no simple method of measuring tumour hypoxia (i.e. a 'biomarker') to predict who will benefit or know if the drugs are working. This makes designing clinical trials challenging, hence no hypoxia-targeted therapies are approved for use in oesophageal cancer. A simple test that measures tumour hypoxia could accelerate clinical trials and make these new drugs available to patients.Solution: Breath testing is safe, acceptable to patients and can be repeated easily. Breath tests are already used in law enforcement to detect blood alcohol levels and in healthcare to diagnose stomach infections (H. pylori) and asthma. At Imperial College London, we have also shown that volatile chemicals in the breath measured using mass spectrometry can accurately diagnose oesophageal cancer. Recent work has shown that some of these chemicals originate from cancer cells and can be influenced by hypoxia. This may mean that we could measure tumour hypoxia through a simple breath test.Aim: The project aim is to develop a non-invasive breath test to predict and monitor the response to hypoxia-targeted therapy in oesophageal cancer.Institutions: This research will be delivered through a strategic collaboration between Imperial College London and Manchester Cancer Research Centre (MCRC). The Volatile Organic Compound (VOC) laboratory at Imperial has recruited more than 3000 patients with cancers of the digestive tract for clinical trials of non-invasive diagnostics over the last 2 years. MCRC has extensive experience in tumour hypoxia research and delivering biomarker-driven trials of hypoxia-targeted therapy.New findings: We have identified: (i) target genes that can be used to detect hypoxia from tumour samples (a hypoxia gene 'signature') and (ii) volatile chemicals that are produced by tumours in response to hypoxia that can be detected in the breath.Project structure: Our aim is to fully characterize the volatile chemicals that are produced by hypoxic tumours and the mechanisms of their production. This will involve analysing volatile chemicals in: (i) breath and cancer tissue from patients retrieved during a camera test ('endoscopy') as part of their routine investigations, and (ii) cancer cells grown under hypoxic and normal conditions. The second aim is to determine how these chemicals change in response to therapy. This will involve analysing: (i) cells grown in a laboratory treated with hypoxia-targeting drugs, and (ii) the breath of oesophageal cancer patients in a clinical trial of a hypoxia-targeting drug.Importance: This project aims to develop a non-invasive breath test to improve patient selection and monitoring of anticancer drugs targeting hypoxia. It is intended that this breath test will accelerate clinical trials to make more effective therapies available to patients. Successful development of a breath test for treatment monitoring would also be the first of its kind worldwide. This innovative approach could promote the concept of breath-based monitoring for a wide range of applications in healthcare.