Developing a breath test for tumour hypoxia in oesophageal adenocarcinoma to aid precision therapy
Lead Research Organisation:
Imperial College London
Department Name: Surgery and Cancer
Abstract
In the UK, over 9000 people are diagnosed with oesophageal cancer each year. Unfortunately, only 15% of these individuals will live beyond 5 years. Whilst chemotherapy and radiotherapy treatments are available for oesophageal cancer, most patients do not respond and are left with a poor prognosis. To improve the quality of life for patients suffering from this cancer of unmet need, new therapeutic strategies are essential.
Cancers grow rapidly and often outstrip their own blood supply, leading to a state of low oxygen levels (known as hypoxia). This hypoxia is an important cause of treatment resistance in oesophageal cancer. Although new drugs targeting hypoxic tumours have been developed, numerous studies have shown only certain patients will respond to these medications. We currently have no clinically acceptable method to measure tumour hypoxia. Existing biomarkers for tumour hypoxia have failed to be translated into clinical practice as they are too expensive, impractical or have limited reproducibility. Therefore, we are unable to identify which patients may benefit from hypoxia targeting drugs. This makes designing clinical trials difficult and consequently there are no hypoxia-targeting agents approved in oesophageal cancer. Designing a practical and scalable test for tumour hypoxia would allow researchers to identify patients who may benefit from hypoxia-targeting medications. This could lead to a wave of new personalised therapies in this patient group.
Our lab has developed a breath test to identify patients with oesophageal cancer. This breath test uses the altered profile of small volatile molecules found in exhaled breath to help diagnose oesophageal cancer. This breath test is safe, simple to perform, easily repeatable and highly acceptable to both patients and the public. Research has shown that some of the volatile molecules detected in breath are generated by cancer cells and are affected by hypoxia. Therefore, we aim to tailor our established breath test to identify which patients are suffering from hypoxic oesophageal tumours, allowing clinicians to predict their response to hypoxia-targeting drugs.
To achieve this, we will build on our preliminary work demonstrating cancer cells exposed to hypoxic conditions produce a distinct volatile organic compound (VOC) signature. First, we will establish the biological pathways underpinning the unique VOC response to hypoxia in oesophageal cancer cells. Then, using our biobank of patient-derived organoids from oesophageal cancer patients, we will verify these cell findings in organoids exposed to hypoxic conditions. Finally, our study in oesophageal cancer patients using the hypoxia-labelling agent Pimonidazole will use human tissue to provide us with a deep understanding of the metabolic and genetic adaptations cancer cells undergo in response to hypoxia. From this information, we will construct a breath test for tumour hypoxia in oesophageal cancer patients using existing patient breath datasets.
An effective hypoxia breath test would be the first of its kind. It will provide researchers with the opportunity to design clinical trials using hypoxia-targeting medications for the patients who will benefit most. This personalised therapeutic strategy could provide new treatments for these patients and improve their survival. The repeatable nature of breath testing means the test could even be used for therapeutic monitoring. The innovative prospect of a hypoxic breath test could advance the oncological management of oesophageal cancer and aid the progress of precision medicine.
Cancers grow rapidly and often outstrip their own blood supply, leading to a state of low oxygen levels (known as hypoxia). This hypoxia is an important cause of treatment resistance in oesophageal cancer. Although new drugs targeting hypoxic tumours have been developed, numerous studies have shown only certain patients will respond to these medications. We currently have no clinically acceptable method to measure tumour hypoxia. Existing biomarkers for tumour hypoxia have failed to be translated into clinical practice as they are too expensive, impractical or have limited reproducibility. Therefore, we are unable to identify which patients may benefit from hypoxia targeting drugs. This makes designing clinical trials difficult and consequently there are no hypoxia-targeting agents approved in oesophageal cancer. Designing a practical and scalable test for tumour hypoxia would allow researchers to identify patients who may benefit from hypoxia-targeting medications. This could lead to a wave of new personalised therapies in this patient group.
Our lab has developed a breath test to identify patients with oesophageal cancer. This breath test uses the altered profile of small volatile molecules found in exhaled breath to help diagnose oesophageal cancer. This breath test is safe, simple to perform, easily repeatable and highly acceptable to both patients and the public. Research has shown that some of the volatile molecules detected in breath are generated by cancer cells and are affected by hypoxia. Therefore, we aim to tailor our established breath test to identify which patients are suffering from hypoxic oesophageal tumours, allowing clinicians to predict their response to hypoxia-targeting drugs.
To achieve this, we will build on our preliminary work demonstrating cancer cells exposed to hypoxic conditions produce a distinct volatile organic compound (VOC) signature. First, we will establish the biological pathways underpinning the unique VOC response to hypoxia in oesophageal cancer cells. Then, using our biobank of patient-derived organoids from oesophageal cancer patients, we will verify these cell findings in organoids exposed to hypoxic conditions. Finally, our study in oesophageal cancer patients using the hypoxia-labelling agent Pimonidazole will use human tissue to provide us with a deep understanding of the metabolic and genetic adaptations cancer cells undergo in response to hypoxia. From this information, we will construct a breath test for tumour hypoxia in oesophageal cancer patients using existing patient breath datasets.
An effective hypoxia breath test would be the first of its kind. It will provide researchers with the opportunity to design clinical trials using hypoxia-targeting medications for the patients who will benefit most. This personalised therapeutic strategy could provide new treatments for these patients and improve their survival. The repeatable nature of breath testing means the test could even be used for therapeutic monitoring. The innovative prospect of a hypoxic breath test could advance the oncological management of oesophageal cancer and aid the progress of precision medicine.
