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》

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》

In vitro drug testing using patient-derived ovarian cancer organoids.

Ovarian cancer is the most lethal gynecological cancer. As the primary treatment, chemotherapy has a response rate of only 60-70% in advanced stages, and even lower as a second-line treatment. Despite guideline recommendations, which drugs will be most effective remains unclear. Thus, a strategy to prioritize chemotherapy options is urgently needed. Cancer organoids have recently emerged as a method for in vitro drug testing. However, limited clinical correlations have been assessed with test results from cancer organoids, particularly in gynecological cancers. We therefore aimed to generate patient-derived organoids (PDOs) of ovarian cancer, to assess their drug sensitivities and correlations with patient clinical outcomes. PDOs were generated from fresh tumors obtained during surgical resection, which was then cultured under matrix gel and appropriate growth factors. Morphological and molecular characterization of PDOs were assessed by phase contrast microscopy and paraffin-embedded histopathology. Expressions of PAX8, TP53, WT1, CK7, and CK20 were tested by immunohistochemical staining and compared with parental tumor tissues and the human protein atlas database. PDOs were subjected to in vitro drug testing to determine drug sensitivity using Titer-Glo® 3D Cell Viability Assay. PDO viability was measured, and area under the curve calculated, to compare responses to various compounds. Correlations were calculated between selected patients' clinical outcomes and in vitro drug testing results. We established 31 PDOs. Among them, 28 PDOs can be expanded, including 15, 11, and 2 from ovarian, endometrial, and cervical cancers, respectively. The PDOs preserved the histopathological profiles of their originating tumors. In vitro drug testing of 10 ovarian cancer PDOs revealed individual differential responses to recommended drugs, and interpersonal heterogeneity in drug sensitivity, even with the same histology type. Among four patients who were platinum sensitive, resistant, or refractory, PDO drug responses correlated well with their clinical courses. In vitro drug testing using ovarian cancer organoids is feasible and correlates well with patient clinical responses. These results may facilitate development of precision chemotherapy and personalized screening for repurposed or new drugs.

Chen LY ，Chou YT ，Liew PL ，Chu LH ，Wen KC ，Lin SF ，Weng YC ，Wang HC ，Su PH ，Lai HC ... -  《Journal of Ovarian Research》

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 ... -  《-》

Evaluation of anticancer agents using patient-derived tumor organoids characteristically similar to source tissues.

Tamura H ，Higa A ，Hoshi H ，Hiyama G ，Takahashi N ，Ryufuku M ，Morisawa G ，Yanagisawa Y ，Ito E ，Imai JI ，Dobashi Y ，Katahira K ，Soeda S ，Watanabe T ，Fujimori K ，Watanabe S ，Takagi M ... -  《-》