Title: Prostate Organoids for Early disease research and Treatments (POET) study
Funder: The Academy of Medical Sciences

Abstract: High-risk localised prostate cancers harbour a 40% 10 year mortality, and require advancements in early disease research to improve diagnosis and treatment. This has been hampered by the lack of relevant model systems which we will seek to address. The development of patient-derived organoids provides a clinically-annotated 3D culture system which is compatible with high-throughput screening and retains genomic and transcriptional heterogeneity seen in patients. While these have been established for advanced metastatic prostate cancers, prostate organoids for early stage disease have not been described. We recently completed single-cell RNA sequencing from a cohort of high-risk localised prostate cancer patients. This revealed a novel subpopulation of, hitherto unidentified, tumour-specific cell types, that are characterised by unique expression patterns, which could be isolated for organoid establishment. We will use cell-surface markers, combined with optimised workflows for the processing of prostate biopsy specimens, to establish a next-generation patient-derived early model system. To achieve this, we will: 1. Isolate distinct cell populations from image-guided prostate biopsies using flow cytometry 2. Validate transcriptional profiles across tumour cell types, and define the dynamic plasticity of transcriptional networks after long-term culture 3. Optimise culture conditions to maintain genomic and transcriptional states of tumour-specific cells 4. Phenotypically characterise tumour-specific cells and evaluate gene-drug interactions from patient-biopsies. In doing so, we will recapitulate the genetic and phenotypic features of patient tumour biology, and demonstrate scientific and clinical utility of our platform. This will include establishing treatment avatars, to evaluate cellular responses to existing and emerging therapies.

Lay abstract: Prostate cancer can be fatal: Prostate cancer is diagnosed in 1 in 8 men during their lifetime. Often these stay confined to the prostate, but in some men, the tumour will go on to spread around the body and cause premature death. We need better ways of detecting and treating these prostate cancers early on, before they spread. We need to help to answer: “will my cancer kill me without treatment?”, and “which treatment do I need?”. In order to address this, scientists need accurate models of early disease to use in the laboratory. How can we study early prostate cancer? The most accurate way would be to grow patient tumours in a dish. This has not been possible until recently. Mini-organs or ‘organoid’ cell models are now being used to grow prostate cancers in 3D. Unlike 2D cell models, organoids more accurately resemble the complexity of human disease. Organoids have been grown from advanced late-stage cancers, but it has not yet been possible to grow organoids from early prostate cancers. Find the ‘deadly’ cells: Prostate tumours are comprised of lots of cells, only some of which cause death. Our recent research, has revealed the identity of this group of ‘deadly’ cells in early-stage prostate cancer. The POET study will involve isolating ‘deadly’ cells from prostate biopsies, and growing them into organoids. We will test the accuracy of our model, including whether we can predict if 10 newly diagnosed men would benefit from existing or emerging trial therapies.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS