To apply for this programme, please visit www.advanced-biomedical-materials-cdt.manchester.ac.uk. Informal enquiries are welcome, to [Email Address Removed].
ABM CDT Human tumours have complex interplay between the extracellular matrix (ECM) and cellular components. The Clarke lab has used patient-derived xenograft (PDX) tumour models in immune-deficient mice to recapitulate complex microenvironments, including the bone metastatic niche (Eyre et al., Nature Comm., 2019). However, PDX models are subject to limitations including a lack of immune function and human tumour interaction with a mouse microenvironment. The need for a superior in vitro alternative is pressing considering the dominance of PDX models as a tool for personalized therapy. 'Xeno-patient' cohorts are the most clinically relevant animal models in cancer drug discovery (Byrne et al., Nature Reviews Cancer, 2017). Even with its limitations, the breast cancer field uses xenograft models routinely. An alternative is to use breast organoids grown in vitro from patient-derived breast cancer cells or xenografts (Sachs et al., Cell, 2018; Guillen et al., BioRxiv, 2021). The organoids will be encapsulated in peptide hydrogels, which we anticipate will be superior to matrigel (gold standard) since its stiffness can be tuned to match breast cancer ECM physical states. The peptide gel technology, will be modified with or without osteogenic factors to model the bone metastatic niche. In addition, human cellular and extracellular matrix components will be introduced with patient-derived breast cancer cells to create a functional and amenable in vitro platform for multiple applications. These applications include investigating bone metastatic breast cancer biology and screening of targeted therapies in clinically relevant patient samples, providing a platform for precision medicine and testing of personalised treatments
Main questions to be answered:
Breast cancer is well characterised in the primary site but less is known about how it changes after spread to the bone, the main site of breast cancer metastasis in advanced disease, accounting for 70% of cases. Metastasis of breast cancer is the main cause of death from the disease and once diagnosed, only 20% of patients survive more than 5 years. Therefore, in vitro modelling of breast cancer in a bone metastatic microenvironment using patient-derived tumour cells is an unmet need that would progress precision cancer medicine to enable therapies to be personalised for individual patient tumours. The questions to be addressed include:
- Do patient-derived breast cancer and xenograft tumour organoids in peptide hydrogels (ManchesterBiogel) maintain their characteristics and responses to standard therapy?
- Can ECM components be incorporated to model the bone metastatic microenvironment?
- Can we tailor the bone metastatic microenvironment with relevant stromal and immune cells?
Addressing these questions will enhance the feasibility of using patient tumour cells grown in relevant microenvironments to test their responses to treatments targeted based on their genomic and molecular sub-type. For example, combining PI3kinase inhibitor drugs with standard endocrine and CDK4/6 inhibitor therapies in estrogen receptor-positive (ER+) luminal sub-type breast cancer carrying PIK3CA mutations.
University of Manchester, Department of Materials - 19 PhD Projects Available
University of Sheffield, Department of Materials Science and Engineering, 7 PhD Projects Available
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