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

在英国，每月大约有1000名女性死于转移性乳腺癌，NHS每年为此花费约1.2亿英镑，而且目前这种疾病是无法治愈的。因此，迫切需要开发新的治疗方法和/或治疗组合。对于缺乏临床标志物ER、PR和HER2的乳腺癌尤其如此，即众所周知难以治疗的三阴性乳腺癌（tnbc）。实体肿瘤，如乳腺癌，通常是缺氧的：由于血管形成不良，它们的核心缺乏良好的氧气供应。缺氧是癌症扩散和化疗耐药的典型驱动因素。然而，针对缺氧激活的关键蛋白（HIF-1）的研究尚未成功。我们发现HIF-1增加了TNBC细胞中的钠水平。在这个项目中，我们将采用一种创新的方法，使用MRI和钠通过离子通道的运动测量（电生理学）来定义TNBC中的钠离子肿瘤微环境。我们将以前所未有的细节绘制肿瘤缺氧和钠的图谱，以了解它们是如何重叠和相互联系的，以及如何利用它们来造福TNBC患者。总的来说，这个项目跨越了最先进的乳腺癌小鼠和组织模型，揭示了一种新的治疗TNBC的治疗方法。在项目的第一部分，我们将使用尖端的多参数MRI结合钠含量和钠通道功能的测量（荧光显微镜和电生理学）来空间表征TNBC中的离子肿瘤微环境。这将为缺氧和钠之间的联系提供证据，从而为开发新的药物治疗提供理论依据。其次，我们将测试缺氧驱动的肿瘤扩散是否依赖于钠通道活性，以及抑制HIF-1和钠通道联合现有化疗对临床结局的影响。最后，我们将探讨缺氧和HIF-1如何调节TNBC中的钠水平，重点关注基因调控和钠通道活性的直接改变。了解这些机制将使我们能够改进未来的药物/抑制剂选择。该项目将全面了解缺氧如何调节TNBC中的钠。它将为扩大对实体肿瘤离子微环境的研究提供坚实的基础，而实体肿瘤本身就是癌症进展和扩散的驱动因素。缺氧和钠之间的联系为开发减缓癌症进展的新治疗组合提供了一个独特的机会。了解靶向钠如何支持当前治疗缺氧肿瘤的方法对于改善患者预后至关重要。这个长期目标是非常可行的，因为我们可以将现有的钠通道药物（例如用于治疗癫痫和心律失常的药物）用于癌症。未来的成功将通过改善患者的预后和乳腺癌护理的生活质量来实现。

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.