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

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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