Targeting ERK5 as a novel approach to ameliorate breast cancer metastasis to the bone

细胞外调节蛋白5(ERK5)是一种基本的细胞信号转导蛋白，在肿瘤的发生发展中起重要作用。临床研究发现ERK5的表达与包括乳腺癌在内的许多癌症的预后之间有很强的因果关系：ERK5信号的增加与转移扩散、无病生存率下降和激素治疗耐药有关。我们已经开发了一组新药来降解ERK5并在一组乳腺癌模型中具有显著的抗转移作用，初步工作表明这种抗转移作用是通过调节免疫环境：免疫细胞的数量、位置和表型来驱动的。然而，我们还没有探索这些新药是否能特异性地影响乳腺癌的骨转移。70%的晚期乳腺癌患者会出现无法治愈的骨转移。这些骨转移具有毁灭性的影响，并与疼痛、骨折、脊髓压迫和危及生命的高钙血症有关。因此，我们寻找新的治疗乳腺癌骨转移的方法是至关重要的。这个项目旨在通过研究我们的新型ERK5抑制剂是否是改善乳腺癌骨转移的新方法来满足这一未得到满足的需求。转移是一个复杂的过程，需要改变原发肿瘤和转移的生态位。该项目将使用尖端方法学，通过使用定制的体外骨骼三维模型和最近开发的模仿患者的体内乳房骨转移模型来概括这一复杂的过程。这个项目提供了获得跨学科技能的机会，从组织工程到体内肿瘤模型，并将：1.更清楚地了解ERK5对骨转移的影响2.确定我们的ERK5药物是否是改善乳腺癌-骨癌转移的新方法，从而将这项研究转化为乳腺癌患者的切实好处

Extracellular-regulated kinase 5 (ERK5) is a fundamental cell signalling protein and plays a critical role in tumour development and progression. Clinical studies revealed a strong causative link between ERK5 expression and prognosis in many cancers including breast: where increased ERK5-signalling correlates with metastatic spread, decreased disease-free survival and resistance to hormone therapy.We have developed a panel of novel drugs that degrade ERK5 and have a marked anti-metastatic effect in a panel of breast cancer models, with initial work suggesting this anti-metastatic effect is driven via modulation of the immune contexture: the number, location and phenotype of immune cells. However, we have not explored if these new drugs could specifically impact on breast cancer metastasis to the bone. 70% of patients with advanced breast cancer develop incurable bone metastases. These bone metastases have devastating effects and are associated with pain, fractures, spinal cord compression and life threatening hypercalcaemia. It is therefore critical we find new treatments for bone metastases in breast cancer patients.This project aims to address this unmet need by investigating if our novel inhibitors of ERK5 are a novel approach to ameliorate breast cancer metastasis to the bone.Metastasis is a complex process, requiring changes in both the primary tumour and the metastatic niche. This project will use cutting-edge methodology to recapitulate this complex process by using bespoke 3D models of bone in vitro and recently developed, patient-mimetic models of breast-bone metastasis in vivo. This project provides the opportunity to acquire interdisciplinary skills spanning tissue engineering to in vivo tumour modelling and will:1. Generate a clearer understanding of the impact of ERK5 on the bone metastatic niche 2. Determine if our ERK5-drugs are a novel way to ameliorate breast-bone cancer metastases, thereby translating this research into tangible benefit for breast cancer patients