Targeting sodium signalling to combat the disease-driving effects of tumour hypoxia

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Approximately 1000 women die of metastatic breast cancer per month in the UK with an annual cost to the NHS of ~£120 million, and it is currently incurable. Thus, there is an urgent unmet medical need to develop new therapies and/or therapeutic combinations. This is particularly true for breast cancers lacking the clinical markers ER, PR and HER2, referred to as triple-negative breast cancers (TNBCs), which are notoriously difficult to treat. Solid tumours, such as breast cancers, are often hypoxic: they lack a good supply of oxygen in their core due to poorly formed blood vessels. Hypoxia is a well characterised driver of cancer spread and resistance to chemotherapy. However, targeting the key protein which is activated by hypoxia (HIF-1) has not been successful. We have found that HIF-1 increases sodium levels in TNBC cells. In this project, we will apply an innovative approach using MRI and measurements of sodium movement through ion channels (electrophysiology) to define the sodium ionic tumour microenvironment in TNBC. We will map tumour hypoxia and sodium in unprecedented detail to understand how they overlap and are interconnected, and how they can be exploited to benefit TNBC patients. Overall, this project spans state-of-the-art mouse and tissue models of breast cancer to reveal a novel therapeutic approach for treating TNBC.In the first part of the project, we will use cutting edge multiparametric MRI combined with measurements of sodium content and sodium channel function (fluorescence microscopy and electrophysiology) to spatially characterise the ionic tumour microenvironment in TNBC. This will extend evidence for a link between hypoxia and sodium, thus providing a rationale for developing new drug treatments. Secondly, we will test whether hypoxia-driven tumour spread is dependent on sodium channel activity, and the effect of inhibiting HIF-1 and sodium channels on clinical outcome when combined with existing chemotherapy. Finally, we will investigate how hypoxia and HIF-1 regulate sodium levels in TNBC, focusing on gene regulation and direct alteration of sodium channel activity. Understanding these mechanisms will enable us to refine future drug/inhibitor choice.This project will deliver a comprehensive understanding of how hypoxia regulates sodium in TNBC. It will provide a strong foundation for broadening research into the ionic microenvironment of solid tumours, which is itself a driver of cancer progression and spread. The connection between hypoxia and sodium presents a unique opportunity to develop new treatment combinations that slow cancer progression. Understanding how targeting sodium can support current therapies in hypoxic tumours is essential to improving patient outcome. This long term goal is highly feasible because we can repurpose existing sodium channel drugs (for example, those used to treat epilepsy and cardiac arrhythmias) to cancer. Future success will be realised through improved patient outcomes and quality of life in breast cancer care.