3D cell culture and high content imaging in combination with an unbiased informatics-based analysis allows an ex vivo approach to acquire a multi-parametric quantitative description of an in vitro 3D tumour phenotype. Patient-derived xenograft (PDX) tumours represent the gold standard of making patient tumours into pre-clinical models. By incorporating cells derived from PDX tumours we can recapitulate the complexity and heterogeneity present in patients and integrate this into our project partner OcellO's established and validated 3D cell culture platform to generate patient-derived organoid (PDO) models. Such an approach has not been established so far for breast cancer and creates a unique opportunity for high throughput 3D screening platforms to reduce and replace PDX model use.
OcellO has established this principle for cancer cell lines and some prototype in vitro PDO models. Here, we aim to develop a panel of in vitro breast PDO cultures. To systematically evaluate in vitro to in vivo correlation of our models, we will focus on the therapeutically challenging breast cancer sub-type-TNBC. In particular this focus and availability of defined PDX material as well as new drug candidates takes into account our laboratory's focus and the clinical need in analysis of our models for the reduction and partial replacement of animal testing. We will focus on PDO-derived assays for the concordance of therapeutic responses to PARP inhibitors in TNBC matched companion PDOs and PDXs. We will also assess whether drug combination strategies involving PARP inhibitors can be interrogated in such PDO systems. By observing the concordance between the results of the in vitro testing from results of "top-candidate" testing in PDX models in vivo we will assess the concordance between these results. This will establish the use of 3D high-throughput tumour phenotype testing as a triage in order to establish whether novel drugs will be taken forward to in vivo pre-clinical testing.