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

靶向 ERK5 作为改善乳腺癌骨转移的新方法

• 批准号: 2897553
• 金额: --
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2897553
• 关键词: Targeting; ERK5; novel; approach; ameliorate

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

细胞外调节激酶5（ERK 5）是一种基本的细胞信号蛋白，在肿瘤的发生和发展中起着关键作用。临床研究揭示了ERK 5表达与许多癌症（包括乳腺癌）预后之间的密切因果关系：其中增加的ERK 5信号传导与转移性扩散、降低的无病存活率和对激素治疗的抗性相关。我们已经开发了一组降解ERK 5的新药，并且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结构（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骨转移。70%的晚期乳腺癌患者发生无法治愈的骨转移。这些骨转移具有破坏性影响，并与疼痛、骨折、脊髓压迫和危及生命的高钙血症相关。因此，我们找到治疗乳腺癌骨转移的新方法至关重要。本项目旨在通过研究我们的新型ERK 5抑制剂是否是改善乳腺癌骨转移的新方法来解决这一未满足的需求。转移是一个复杂的过程，需要改变原发肿瘤和转移小生境。该项目将使用尖端的方法，通过使用体外骨骼的定制3D模型和最近开发的体内胸骨转移的模拟患者模型来概括这一复杂的过程。该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建模，并将：1。更清楚地了解ERK 5对骨转移灶的影响2.确定我们的ERK5药物是否是改善乳腺癌转移的新方法，从而将这项研究转化为乳腺癌患者的切实利益