Augmentation of Volatile Biomarkers of Oesophageal Adenocarcinoma from the Tumour Lipidome

点击翻译按钮获取中文摘要

Nearly 10,000 patients die each year in the United Kingdom from cancer of the lower gullet, known as oesophageal adenocarcinoma (OAC). OAC is detected late as symptoms are non- specific and often mistaken for common problems such as heartburn. This translates to fewer than 2 in every 10 patients diagnosed with OAC living longer than 5 years. This highlights the urgent need for a test that can accurately detect OAC early, safely and can be used by all patients. The breath of OAC patients is enriched with volatile chemicals (VCs) that indicate cancer. When measured in a breath test, it detects OAC 80 out of 100 times. Whilst encouraging, the detection rate can be improved by using an external stimulant, such as a drink, that amplifies the production of tumour specific VCs only, to increase their levels in breath and improve detection in the breath test. This enables direct comparison of breath samples from the same patient (pre and post stimulant) rather than comparison with others, which improves the reliability of the test. This is known as 'augmentation' and is our novel approach to improving the ability of the breath test to detect OAC, especially early-stage OAC when the cancer is small. To augment OAC VCs, we must target the mechanisms behind their production and enhance this pathway. Lipids are essential to healthy cell structure however the lipids in OAC are reprogrammed to acquire a different composition which leaves them vulnerable to breakdown via process known as 'peroxidation'. This includes breakdown of bacterial lipids associated with the cancer. Lipid peroxidation is considered a main mechanism for producing VCs in humans. This suggests OAC lipids and/ or OAC bacterial lipids are selectively unstable and breakdown to generate VCs that are detected in breath; however, this has not been proven. If true, this process may be augmented with a simple stimulant that promotes this breakdown. To test this theory, I developed a robust way to break lipids from the cells of OAC patients and analyse the VCs generated. Results showed i) lipids break down spontaneously to generate VCs; ii) this process was enhanced with OAC lipids in comparison to healthy lipids, indicating their instability in cancer; iii) the VCs produced from OAC lipids are the same ones detected in the breath of OAC patients and iv) augmentation of OAC lipids using a stimulant solution profoundly increased the quantity of diagnostic VCs produced. These findings suggest that VCs detected in the breath test originate from OAC lipids and this process can be augmented. The overall aim of this project is to produce an improved second-generation breath test with superior ability to detect OAC with augmentation. This will improve long term patient survival from cancer using an entirely non- invasive test. This proposal will be achieved through three interconnected phases. Phase 1 will comprehensively identify the lipid species in OAC tumours that produce VCs using bespoke mass spectrometry techniques custom designed for this purpose. The identified lipids will be used in Phase 2 for 'stable isotope experiments' in OAC patients. These experiments track the breakdown of lipids to VC conversion from root to branch. These experiments will be performed in augmented conditions to evaluate the effect of augmentation on VCs and identify the optimal augmentation approach. Phase 3 will translate the scientific knowledge to benefit patients. Patients will be given an optimised stimulant drink and their breath will be sampled before and after consumption. Patient feedback will be obtained that will heavily influence the design of the breath test. With this second-generation breath test, patients with vague symptoms can undergo a quick, non- invasive test, have samples analysed in a safe and accurate manner and be subsequently stratified based on their risk of having OAC, leading to earlier OAC detection and improved clinical outcomes.