Patient derived organoids in prostate cancer: improving therapeutic efficacy in precision medicine.

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.

Pamarthy S ，Sabaawy HE 《Molecular Cancer》

Development of Patient-Derived Gastric Cancer Organoids from Endoscopic Biopsies and Surgical Tissues.

Gao M ，Lin M ，Rao M ，Thompson H ，Hirai K ，Choi M ，Georgakis GV ，Sasson AR ，Bucobo JC ，Tzimas D ，D'Souza LS ，Buscaglia JM ，Davis J ，Shroyer KR ，Li J ，Powers S ，Kim J ... -  《-》

Patient-derived organoids model treatment response of metastatic gastrointestinal cancers.

Patient-derived organoids (PDOs) have recently emerged as robust preclinical models; however, their potential to predict clinical outcomes in patients has remained unclear. We report on a living biobank of PDOs from metastatic, heavily pretreated colorectal and gastroesophageal cancer patients recruited in phase 1/2 clinical trials. Phenotypic and genotypic profiling of PDOs showed a high degree of similarity to the original patient tumors. Molecular profiling of tumor organoids was matched to drug-screening results, suggesting that PDOs could complement existing approaches in defining cancer vulnerabilities and improving treatment responses. We compared responses to anticancer agents ex vivo in organoids and PDO-based orthotopic mouse tumor xenograft models with the responses of the patients in clinical trials. Our data suggest that PDOs can recapitulate patient responses in the clinic and could be implemented in personalized medicine programs.

Vlachogiannis G ，Hedayat S ，Vatsiou A ，Jamin Y ，Fernández-Mateos J ，Khan K ，Lampis A ，Eason K ，Huntingford I ，Burke R ，Rata M ，Koh DM ，Tunariu N ，Collins D ，Hulkki-Wilson S ，Ragulan C ，Spiteri I ，Moorcraft SY ，Chau I ，Rao S ，Watkins D ，Fotiadis N ，Bali M ，Darvish-Damavandi M ，Lote H ，Eltahir Z ，Smyth EC ，Begum R ，Clarke PA ，Hahne JC ，Dowsett M ，de Bono J ，Workman P ，Sadanandam A ，Fassan M ，Sansom OJ ，Eccles S ，Starling N ，Braconi C ，Sottoriva A ，Robinson SP ，Cunningham D ，Valeri N ... -  《-》

Development of a Single-Cell Technique to Increase Yield and Use of Gastrointestinal Cancer Organoids for Personalized Medicine Application.

Organoids are excellent 3-dimensional in vitro models of gastrointestinal cancers. However, patient-derived organoids (PDOs) remain inconsistent and unreliable for rapid actionable drug sensitivity testing due to size variation and limited material. On day10/passage 2 after standard creation of organoids, half of PDOs were dissociated into single-cells with TrypLE Express Enzyme/DNase I and mechanical dissociation; and half of PDOs were expanded by the standard technique. Hematoxylin and eosin and immunohistochemistry with CK7 and CK20 were performed for characterization. Drug sensitivity testing was completed for single-cells and paired standard PDOs to assess reproducibility. After 2 to 3 days, >50% of single-cells reformed uniform miniature PDOs (∼50 μm). We developed 10 PDO single-cell lines (n = 4, gastric cancer, [GC]; and n = 6, pancreatic ductal adenocarcinoma, [PDAC]), which formed epithelialized cystic structures and by IHC, exhibited CK7(high)/CK20(low) expression patterns mirroring parent tissues. Compared with paired standard PDOs, single-cells (n = 2, PDAC; = 2, GC) showed similar architecture, albeit smaller and more uniform. Importantly, single cells demonstrated similar sensitivity to cytotoxic drugs to matched PDOs. PDO single-cells are accurate for rapid clinical drug testing in gastrointestinal cancers. Using early passage PDO single-cells facilitates high-volume drug testing, decreasing time from tumor sampling to actionable clinical decisions, and provides a personalized medicine platform to optimally select drugs for gastrointestinal cancer patients.

Gao M ，Harper MM ，Lin M ，Qasem SA ，Patel RA ，Mardini SH ，Gabr MM ，Cavnar MJ ，Pandalai PK ，Kim J ... -  《-》

Patient-Derived Ovarian Cancer Organoids Mimic Clinical Response and Exhibit Heterogeneous Inter- and Intrapatient Drug Responses.

There remains an unmet need for preclinical models to enable personalized therapy for ovarian cancer (OC) patients. Here we evaluate the capacity of patient-derived organoids (PDOs) to predict clinical drug response and functional consequences of tumor heterogeneity. We included 36 whole-genome-characterized PDOs from 23 OC patients with known clinical histories. OC PDOs maintain the genomic features of the original tumor lesion and recapitulate patient response to neoadjuvant carboplatin/paclitaxel combination treatment. PDOs display inter- and intrapatient drug response heterogeneity to chemotherapy and targeted drugs, which can be partially explained by genetic aberrations. PDO drug screening identifies high responsiveness to at least one drug for 88% of patients. PDOs are valuable preclinical models that can provide insights into drug response for individual patients with OC, complementary to genetic testing. Generating PDOs of multiple tumor locations can improve clinical decision making and increase our knowledge of genetic and drug response heterogeneity.

de Witte CJ ，Espejo Valle-Inclan J ，Hami N ，Lõhmussaar K ，Kopper O ，Vreuls CPH ，Jonges GN ，van Diest P ，Nguyen L ，Clevers H ，Kloosterman WP ，Cuppen E ，Snippert HJG ，Zweemer RP ，Witteveen PO ，Stelloo E ... -  《Cell Reports》