Abstract
With advances in the discovery of the clinical and molecular landscapes of prostate cancer (PCa), implementation of precision medicine-guided therapeutic testing in the clinic has become a priority. Patient derived organoids (PDOs) are three-dimensional (3D) tissue cultures that promise to enable the validation of preclinical drug testing in precision medicine and coclinical trials by modeling PCa for predicting therapeutic responses with a reliable efficacy. We evaluate the advances in 3D culture and PDO use to model clonal heterogeneity and screen for effective targeted therapies, with a focus on the technological advances in generating PDOs. Recent innovations include the utilization of PDOs both in original research and/or correlative studies in clinical trials to examine drug effects within the PCa tumor microenvironment (TME). There has also been a significant improvement with the utilization of various extracellular matrices and single cell assays for the generation and long-term propagation of PDOs. Single cell derived PDOs could faithfully recapitulate the original tumor and reflect the heterogeneity features. While most PDO use for precision medicine understandably involved tissues derived from metastatic patients, we envision that the generation of PDOs from localized PCa along with the incorporation of cells of the TME in tissue models would fulfill the great potential of PDOs in predicting drug clinical benefits. We conclude that single cell derived PDOs reiterate the molecular features of the original tumor and represent a reliable pre-clinical PCa model to understand individual tumors and design tailored targeted therapies.
Highlights
Patient derived preclinical models Various preclinical models have been used to advance prostate cancer (PCa) research
Successful generation of Patient-derived xenografts (PDX) for drug screening takes several months to accomplish [5, 6]. Both PDXs and PCa cell lines are frequently derived from the aggressive metastatic disease and there is a paucity of preclinical models for studying primary locoregional PCa
With the increased understanding of the origin and the molecular landscape of PCa, there has been an encouraging trend of precision medicine-based approach to treat advanced PCa
Summary
Prostate cancer (PCa) is the second most frequent cancer diagnosed in men worldwide, only behind lung cancer. While the past decade has seen an accelerated decline in the death rate of lung cancer, reduction rate halted for PCa [1]. Progress on the use of such molecular-biomarkers for treatment selection in the clinic has been hampered by the limited access to tumor tissue for molecular profiling, the lack of reliable approaches to capture tumor heterogeneity at different disease states, and the imperfect preclinical models [3]. We summarize the past, present, and future of prostate PDOs, outlining how PCa PDOs can be used to improve the therapeutic decisionmaking process and guide the selection of sequential or combinatorial therapies for the metastatic disease
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