Hypoxia Driven Metabolic Response in Oesophagogastric Adenocarcinoma (HYDRA)

Oesophagogastric Cancer and Hypoxia:

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

Tumour hypoxia occurs when rapidly growing malignancies outstrip oxygen (and nutrient) supply. 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. Reassuringly, there are emerging treatment options available. The adaptive pathways triggered by hypoxia offer unique opportunities for personalized and targeted oncological therapies to improve clinical outcomes in this patient cohort. However, for these therapies to be effective, it is vital patients with hypoxic tumours can be identified.

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.

Volatile Organic Compounds and Breath:

The Hanna Group at Imperial College London has developed a non-invasive breath test for the diagnosis of oesophagogastric adenocarcinoma through the detection of exhaled Volatile Organic Compounds (VOCs). This was validated in a multi-centre NIHR-funded clinical study that demonstrated 80% sensitivity and 81% specificity. In parallel with this work, the exhalation kinetics and molecular drivers of VOCs in oesophagogastric adenocarcinoma have also been investigated. It has been understood that the VOCs that can be detected in blood, breath, urine, and saliva are a representation of the metabolic and microbiotic changes that occur in the tumour and its microenvironment.

Rationale for Study:

There is a clear unmet need for a dynamic non-invasive test to identify patients suffering with hypoxic oesophagogastric tumours. 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 oncological therapies for these patients. Furthermore, the reproducibility and patient acceptability make a breath test an ideal testing method for dynamic hypoxia monitoring .

Promising work within the Hanna Group has already demonstrated the potential viability of a 'hypoxia breath test'. Early cell culture experiments and pilot studies have demonstrated hypoxic tumours release discriminatory VOCs which could be leveraged as hypoxic biomarkers.

HYDRA Study

The HYDRA study is a single-centre observational study at Imperial College London with the aim of devising a non-invasive breath test for OG tumour hypoxia. The study contains two arms: the Pimonidazole and Biosampling arm.

In the Pimonidazole arm, 20 participants (10 oesophageal and 10 gastric cancer) 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 and spatial metabolomic techniques. This will allow the creation of an OG-hypoxic gene signature.

The Biosampling arm will recruit 100 patients undergoing OG cancer surgery. Participants will undergo breath sampling and intra-operative tumour sampling. Using the 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 OG breath test, separating patients with hypoxia-high and hypoxia-low tumours.

Study Overview

• Status: Recruiting
• Conditions: OESOPHAGO-GASTRIC CARCINOMA
• Intervention / Treatment: Drug: Pimonidazole hydrochloride (Hypoxyprobe™-1)

• Study Type: Observational
• Enrollment (Estimated): 120

Contacts and Locations

• Study Contact: Name: Henry Douglas Robb, MBChB BSc (Hons) MSc MRCS; Phone Number: +44 (0) 207 594 8847; Email: henry.robb19@imperial.ac.uk

Study Locations

• United Kingdom
  • London, United Kingdom
    • Recruiting
    • Imperial College NHS Healthcare Trust
    • Contact: Henry Robb, MBChB BSc (Hons) MSc MRCS; Phone Number: 44 (0) 207 594 8847

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Oesophago-gastric patients undergoing surgery on their cancer

Description

Inclusion Criteria:

• Male and females aged 18-90 years.
• Patients with biopsy proven oesophageal or gastric adenocarcinoma who are undergoing either surgical resection or staging laparoscopy.

Exclusion Criteria:

• Non-adenocarcinoma cancer (e.g. oesophageal squamous cell carcinoma)
• Antibiotic therapy within the last 8 weeks
• Previous oesophageal and gastric resection
• Allergy to pimonidazole
• Unable or unwilling to provide informed written consent
• Pregnant women

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Pimonidazole Group; Will receive Pimonidazole (as a non-CTIMP) to enable hypoxic tumour stratification	Drug: Pimonidazole hydrochloride (Hypoxyprobe™-1); Participants will receive Pimonidazole (non-CTIMP) prior to their surgery for OG cancer and then undergo intra-operative sampling.
Biosampling Group; Participants will undergo blood, urine and breath sampling on their morning of their surgery on their OG tumour. Intra-operatively, tumour samples will be taken.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Volatile Organic Compounds Breath Signature	Bulk RNAseq will be performed on tumour samples from Biosampling participants. Participants will then be classified by their hypoxic score using the previously derived hypoxic gene signature. Distinguishing Volatile Organic Compounds (VOCs) detected in exhaled breath, using GC-MS, between these two groups will generate an OAC hypoxic breath profile.	5 years
Hypoxic Gene Signature	Spatial transcriptomic, lipidomic and pathway analysis on pimonidazole-labelled tissue will allow the identification of a OAC hypoxic gene signature.	5 years

Collaborators and Investigators

• Sponsor: Imperial College London
• Investigators: Principal Investigator: George Hanna, Imperial College London; Study Director: Henry Robb, MBChB BSc (Hons) MSc MRCS, Imperial College London; Study Chair: Bibek Das, MBChB, Imperial College London

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2024
• Primary Completion (Estimated): August 1, 2028
• Study Completion (Estimated): August 1, 2028

Study Registration Dates

• First Submitted: October 30, 2024
• First Submitted That Met QC Criteria: October 30, 2024
• First Posted (Actual): November 1, 2024

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 5, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: hypoxia; volatile organic compounds; breath test; pimonidazole; voc; oesophago-gastric carcinoma
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Stomach Diseases; Neoplasms, Glandular and Epithelial; Carcinoma; Signs and Symptoms, Respiratory; Stomach Neoplasms; Hypoxia; Adenocarcinoma
• Other Study ID Numbers: 324771; MR/Z504142/1 (Other Grant/Funding Number: Medical Research Council); 23/PR/0723 (Registry Identifier: Human Research Authority (HRA) Research Ethics Council (REC))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No