HYDRA

HYpoxia Driven metabolic Response in esophagogastric Adenocarcinoma


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Oesophagogastric cancer is a significant global burden, with 1.7 million new cases per year. Outcomes for oesophagogastric cancer is poor, with the five-year survival for these cancers in the UK being between 15-20%, which is amongst the lowest in Europe. The reason for this poor survival is due to late diagnosis and treatment-resistant hypoxic tumours, both significantly contributing to this high mortality.

Tumour hypoxia occurs when rapidly growing tumours can no longer support their increasing oxygen (and nutrient) needs. These hypoxic conditions trigger adaptive metabolic and genomic mutations within the cancer. Clinically, these mutations lead to cancers which are highly aggressive and treatment resistant. Therefore, patients with oesophagogastric cancers displaying high degrees of hypoxia have a considerably poorer prognosis. The adaptive pathways triggered by hypoxia offer unique opportunities for personalised and targeted therapies to improve clinical outcomes in this subgroup of patients. However, for these therapies to be effective, it is vital that patients with hypoxic tumours can be identified early.

There are currently no established methods for identifying hypoxic tumours in oesophagogastric cancer patients. Whilst biomarker candidates have been identified, these require invasive biopsies and are limited in terms of repeatability, and therefore, clinical applicability. There is hope in developing non-invasive hypoxic imaging, however, considerable validation work is required prior to their clinical introduction for oesophagogastric patients.

There is a clear unmet need for a dynamic non-invasive test to identify patients with hypoxic oesophagogastric tumours. Our group has developed a non-invasive breath test for the diagnosis of oesophagogastric adenocarcinoma through the detection of exhaled volatile organic compounds (VOCs). By adapting the breath test model, it is believed that patients with hypoxic tumours can be effectively detected. This creates the opportunity to offer targeted therapies for these patients. Furthermore, the reproducibility and patient acceptability make a breath test an ideal testing method for dynamic hypoxia monitoring.

Aims:

1. Utilise spatial transcriptomic, lipidomic, and pathway analysis to identify an oesophagogastric-hypoxic gene signature.

2. Develop a hypoxic-oesophagogastric breath test to identify patients with hypoxia-high and hypoxia-low tumours.

Methods:

HYDRA is a single-centre observational study at Imperial College London. Patients who are undergoing surgery for oesophageal-gastric cancer, aged 18 or above are eligible for recruitment. The study will have 2 arms, the Pimonidazole arm is 10 patients and the Biosampling arm is 100 patients.

The Pimonidazole arm will be given Pimonidazole (Hypoxyprobe Inc.), a hypoxia-labelling agent, prior to their surgery for oesophagogastric cancer. Hypoxia-stratified tissue will be sampled intraoperatively and analysed using spatial transcriptomics (GeoMx) and spatial metabolomic (DESI-MS) techniques. This will allow the creation of an oesophagogastric-hypoxic gene signature.

The Biosampling arm will undergo breath sampling and intraoperative tumour sampling. Using the oesophagogastric-hypoxic gene signature generated in the Pimonidazole arm, transcriptomic analysis of tumour samples will allow patient categorisation into hypoxia-high and hypoxia-low subgroups. This will enable our group to devise a hypoxic-oesophageal cancer breath test, identifying patients with hypoxia-high and hypoxia-low tumours.

Study design:

Participating centres:

For more information relating to the study, please get in touch with Mr Henry Robb, via email: henry.robb19@imperial.ac.uk