Volatile hypoxia signatures in oesophageal adenocarcinoma

食管腺癌中的挥发性缺氧特征

• 批准号: MR/V02955X/1
• 负责人: Bibek Das
• 金额: $ 27.17万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV02955X%2F1
• 关键词: Volatile; hypoxia; signatures; oesophageal; adenocarcinoma

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.

临床需求：在英国，每年有9，200名患者被诊断患有食道癌，但100名患者中只有15名可以预期寿命超过5年。大多数患者对化疗或放疗没有反应，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。肿瘤中的缺氧（“缺氧”）是治疗抵抗的原因。已经开发出有前途的新药，可以减少缺氧，改善患者的预后。然而，以前的研究表明，只有某些缺氧肿瘤患者会有反应。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。一个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，可以很容易地重复。呼吸测试已经用于执法，以检测血液酒精含量和医疗保健，以诊断胃部感染（H。pylori）和哮喘。在伦敦帝国理工学院，我们还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管癌。最近的研究表明，这些化学物质中的一些来自癌细胞，并可能受到缺氧的影响。这可能意味着我们可以通过一个简单的呼吸测试来测量肿瘤缺氧。目的：该项目的目的是开发一种无创呼吸测试来预测和监测食管癌对缺氧靶向治疗的反应。机构：这项研究将通过帝国理工学院伦敦和曼彻斯特癌症研究中心（MCRC）之间的战略合作来实现。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）可用于检测肿瘤样品中缺氧的靶基因（一种缺氧基因“特征”）和（ii）呼吸中可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”）期间检索的患者的呼吸和癌组织，作为其常规调查的一部分，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如何响应治疗而变化。这将涉及分析：（i）在实验室用低氧靶向药物治疗的细胞，和（ii）在低氧靶向药物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非侵入性呼吸测试，以改善患者选择和监测靶向低氧的抗癌药物。该呼吸测试旨在加速临床试验，为患者提供更有效的治疗方法。成功开发用于治疗监测的呼吸测试也将是世界上第一个此类测试。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中的广泛应用。

项目成果

A novel prognostic hypoxia gene signature identifies de novo nucleotide synthesis as a metabolic vulnerability in gastric cancer

一种新的预后缺氧基因特征将核苷酸从头合成确定为胃癌的代谢脆弱性

• DOI: 10.1016/j.ejso.2022.11.025
• 发表时间: 2023
• 期刊: European Journal of Surgical Oncology
• 作者: Das B

Unique volatile signatures of gastrointestinal cancers suggest cell autonomous drivers of metabolic reprogramming with potential for non-invasive diagnosis

胃肠癌独特的挥发性特征表明代谢重编程的细胞自主驱动因素具有非侵入性诊断的潜力

• DOI: 10.1016/j.ejso.2022.11.027
• 发表时间: 2023
• 期刊: European Journal of Surgical Oncology
• 作者: Leung P

Prognostic and Predictive Utility of GPD1L in Human Hepatocellular Carcinoma.

• DOI: 10.3390/ijms241713113
• 发表时间: 2023-08-23
• 期刊: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
• 影响因子: 5.6
• 作者: Leung, Philip K. H.;Das, Bibek;Cheng, Xiaoyu;Tarazi, Munir
• 通讯作者: Tarazi, Munir