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

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.

There is an urgent need to develop new therapies or therapeutic combinations for triple negative breast cancer (TNBC). We present a unique approach that will leverage the ionic (chemical, non-protein) tumour microenvironment to deliver new, independent therapeutic approaches that can be harnessed to improve outcomes for cancer patients.

Our data show that physiological and biochemical changes in TNBC tumours lead to accumulation of intracellular sodium (Na+). This altered Na+ environment promotes tumour spread and we have demonstrated that suppressing Na+ transport by blocking the Nav1.5 channel inhibits metastasis. Recently, our analysis has shown that HIF-1 regulates Nav1.5 expression and function, defining an exploitable link between hypoxia and Na+ transport. We propose that this previously undescribed hypoxia/Na+ signalling axis represents a new and highly tractable targetable pathway.

This project will deliver a comprehensive understanding of how hypoxia impacts on Na+ in the tumour microenvironment, focusing on Nav1.5 as a key Na+ transporting intermediary in this mechanism. We will also evaluate potential redundancy among Na+ transporters that could function as escape pathways, moving the state of the art beyond consideration of specific channels in isolation, towards an integrated model of the tumour Na+ transportome.

This will be the first integrated mechanistic study of Na+ and hypoxia in malignant disease. The hypoxia-Na+ signalling axis presents a significant opportunity to develop novel treatment combinations that slow malignant progression. These combinations are likely to be more effective than targeting HIF-1 alone, given the inherent accessibility and pharmacological tractability of plasma membrane Na+ transporters. Understanding how targeting Na+ can support current therapies in hypoxic tumours is essential to improving patient outcome and is highly feasible due to the potential to repurpose existing Na+ transport-inhibiting drugs.