An open, non-interventional study based on the drug sensitivity detection technology of tumor patient-derived organoids
Ontology highlight
ABSTRACT:
DISEASE(S): Colorectal Cancer
PROVIDER: 2734714 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:BackgroundPatient-derived organoids (PDOs) from advanced colorectal cancer (CRC) patients could be a key platform to predict drug response and discover new biomarkers. We aimed to integrate PDO drug response with multi-omics characterization beyond genomics.MethodsWe generated 29 PDO lines from 22 advanced CRC patients and provided a morphologic, genomic, and transcriptomic characterization. We performed drug sensitivity assays with a panel of both standard and non-standard agents in five long-term cultures, and integrated drug response with a baseline proteomic and transcriptomic characterization by SWATH-MS and RNA-seq analysis, respectively.ResultsPDOs were successfully generated from heavily pre-treated patients, including a paired model of advanced MSI high CRC deriving from pre- and post-chemotherapy liver metastasis. Our PDOs faithfully reproduced genomic and phenotypic features of original tissue. Drug panel testing identified differential response among PDOs, particularly to oxaliplatin and palbociclib. Proteotranscriptomic analyses revealed that oxaliplatin non-responder PDOs present enrichment of the t-RNA aminoacylation process and showed a shift towards oxidative phosphorylation pathway dependence, while an exceptional response to palbociclib was detected in a PDO with activation of MYC and enrichment of chaperonin T-complex protein Ring Complex (TRiC), involved in proteome integrity. Proteotranscriptomic data fusion confirmed these results within a highly integrated network of functional processes involved in differential response to drugs.ConclusionsOur strategy of integrating PDOs drug sensitivity with SWATH-mass spectrometry and RNA-seq allowed us to identify different baseline proteins and gene expression profiles with the potential to predict treatment response/resistance and to help in the development of effective and personalized cancer therapeutics.
| S-EPMC9817273 | biostudies-literature
Project description:Interventions: Case series:Nil
Primary outcome(s): Survival
Study Design: Sequential
| 2689769 | ecrin-mdr-crc
Project description:Patient-derived tumor organoids (PDOs) hold immense potential for personalized drug sensitivity testing, but accurate efficacy determination is crucial for clinical translation. This study investigated factors influencing the accuracy and reproducibility of drug sensitivity measurements in PDOs, focusing on half-maximal-inhibitory-concentration (IC50) calculation methods, drug concentration numbers, and plate types. PDOs were established from six primary cancer tissues, including two cervical resections, one lung biopsy, one lung pleural effusion, one breast biopsy, and one gastric resection. They were subjected to drug sensitivity assays with 21 single/combined treatments, encompassing chemotherapy and targeted therapy drugs, with concentrations standardized in fold. Utilizing 6- and 12-concentration setups, IC50 derived from GraphPad-Dose-response-Inhibition (DRI), LC-logit, and LC-probit methods were compared. Relative changes (RCs) in IC50 and area-under-the dose-response-curve (AUC) between setups and the impact of plate type on cell viability measurements were assessed. In the 12-concentration setup, no significant IC50 differences were observed among the calculation methods. Notably, GraphPad-DRI and LC-logit exhibited minimal RCs between the 6- and 12-concentration setups (0.035 and -0.033, respectively), indicating accurate IC50 quantification even with fewer drug concentrations. AUC correlated strongly with GraphPad-DRI-derived IC50 (R = 0.858) and demonstrated lower variance between technical replicates. Furthermore, opaque-bottom plates yielded higher precision in cell viability measurements compared to transparent-bottom plates. This study provides valuable insights into optimizing drug sensitivity testing in PDOs. By demonstrating the robustness of specific IC50 calculation methods and the feasibility of using fewer drug concentrations, this study contributed to the standardization and reliability of PDO-based drug sensitivity assays.
| S-EPMC11890276 | biostudies-literature
Project description:Patient-derived tumor organoids (PDTOs) have the potential to be used to predict the patient response to chemotherapy. However, the cutoff value of the half-maximal inhibition concentration (IC50) for PDTO drug sensitivity has not been validated with clinical cohort data. We established PDTOs and performed a drug test in 277 samples from 242 CRC patients who received FOLFOX or XELOX chemotherapy. After follow-up and comparison of the PDTO drug test and final clinical outcome results, the optimal IC50 cutoff value for PDTO drug sensitivity was 43.26 μmol/L. This PDTO drug test-defined cutoff value could predict patient response with 75.36% sensitivity, 74.68% specificity, and 75% accuracy. Moreover, this value distinguished groups of patients with significant differences in survival benefit. Our study is the first to define the IC50 cutoff value for the PDTO drug test to effectively distinguish CRC patients with chemosensitivity or nonsensitivity and predict survival benefits.
| S-EPMC10329174 | biostudies-literature
Project description:Most cancer treatment strategies target cell proliferation, angiogenesis, migration, and intravasation of tumor cells in an attempt to limit tumor growth and metastasis. An in vitro platform to assess tumor progression and drug sensitivity could provide avenues to enhance our understanding of tumor metastasis as well as precision medicine. We present a microfluidic platform that mimics biological mass transport near the arterial end of a capillary in the tumor microenvironment. A central feature is a quiescent perfused 3D microvascular network created prior to loading tumor cells or patient-derived tumor organoids in an adjacent compartment. The physiological delivery of nutrients and/or drugs to the tumor then occurs through the vascular network. We demonstrate the culture, growth, and treatment of tumor cell lines and patient-derived breast cancer organoids. The platform provides the opportunity to simultaneously and dynamically observe hallmark features of tumor progression including cell proliferation, angiogenesis, cell migration, and tumor cell intravasation. Additionally, primary breast tumor organoids are viable in the device for several weeks and induce robust sprouting angiogenesis. Finally, we demonstrate the feasibility of our platform for drug discovery and personalized medicine by analyzing the response to chemo- and anti-angiogenic therapy. Precision medicine-based cancer treatments can only be realized if individual tumors can be rapidly assessed for therapeutic sensitivity in a clinically relevant timeframe (⪅14 days). Our platform indicates that this goal can be achieved and provides compelling opportunities to advance precision medicine for cancer.
| S-EPMC10644986 | biostudies-literature
Project description:Understanding the phenotypic alterations that play a role in differential response to drugs will be pivotal in identifying predictive biomarkers and developing efficacious therapies for advanced CRC. The bulk of research to date has focused on the value of organoids as a predictive tool; some have characterized the transcriptomic profile in relation to drug sensitivity in an effort to identify predictive biomarkers, but only a limited number of studies have used quantitative proteomic analysis to characterize PDOs. Extensive literature indicates that transcriptomic and proteomic expression profiles lack correlation due to significant post-transcriptional regulation, which could explain why RNA signatures are rarely useful as drug response predictors in the clinic. In this study we generated PDO models from advanced CRC patients including heavily pre-treated patients and a model of microsatellite instable- (MSI) high CRC, for which pre- and post chemotherapy liver disease PDOs were established and characterized to ensure biological fidelity with the original tumors. Our main objective was to integrate functional drug assays on PDOs with proteotranscriptomic study to explore the mechanisms underlying drug response. To this end, we used SWATH-MS (sequential window acquisition of all theoretical mass spectrometry), a highly accurate proteomic quantification technique and a bulk RNA-seq analysis. This strategy could represent a useful tool to discover new therapeutic targets in advanced CRC and to guide personalized therapies.
2025-02-03 | PXD038149 | Pride
Project description:BackgroundTreatment resistance and tumor relapse are the primary causes of mortality in glioblastoma (GBM), with intratumoral heterogeneity playing a significant role. Patient-derived cancer organoids have emerged as a promising model capable of recapitulating tumor heterogeneity. Our objective was to develop patient-derived GBM organoids (PGO) to investigate treatment response and resistance.MethodsGBM samples were used to generate PGOs and analyzed using whole-exome sequencing (WES) and single-cell karyotype sequencing. PGOs were subjected to temozolomide (TMZ) to assess viability. Bulk RNA sequencing was performed before and after TMZ.ResultsWES analysis on individual PGOs cultured for 3 time points (1-3 months) showed a high inter-organoid correlation and retention of genetic variants (range 92.3%-97.7%). Most variants were retained in the PGO compared to the tumor (range 58%-90%) and exhibited similar copy number variations. Single-cell karyotype sequencing demonstrated preservation of genetic heterogeneity. Single-cell multiplex immunofluorescence showed maintenance of cellular states. TMZ treatment of PGOs showed a differential response, which largely corresponded with MGMT promoter methylation. Differentially expressed genes before and after TMZ revealed an upregulation of the JNK kinase pathway. Notably, the combination treatment of a JNK kinase inhibitor and TMZ demonstrated a synergistic effect.ConclusionsOverall, these findings demonstrate the robustness of PGOs in retaining the genetic and phenotypic heterogeneity in culture and the application of measuring clinically relevant drug responses. These data show that PGOs have the potential to be further developed into avatars for personalized adaptive treatment selection and actionable drug target discovery and as a platform to study GBM biology.
| S-EPMC10733660 | biostudies-literature
Project description:The use of primary patient-derived organoids for drug sensitivity and resistance testing could play an important role in precision cancer medicine. We developed expandable ovarian cancer organoids in < 3 weeks; these organoids captured the characteristics of histological cancer subtypes and replicated the mutational landscape of the primary tumours. Seven pairs of organoids (3 high-grade serous, 1 clear cell, 3 endometrioid) and original tumours shared 59.5% (36.1-73.1%) of the variants identified. Copy number variations were also similar among organoids and primary tumours. The organoid that harboured the BRCA1 pathogenic variant (p.L63*) showed a higher sensitivity to PARP inhibitor, olaparib, as well as to platinum drugs compared to the other organoids, whereas an organoid derived from clear cell ovarian cancer was resistant to conventional drugs for ovarian cancer, namely platinum drugs, paclitaxel, and olaparib. The overall success rate of primary organoid culture, including those of various histological subtypes, was 80% (28/35). Our data show that patient-derived organoids are suitable physiological ex vivo cancer models that can be used to screen effective personalised ovarian cancer drugs.
| S-EPMC7387538 | biostudies-literature
Project description:Patient-derived organoids (PDOs) have shown the potential to reflect patient sensitivity to chemotherapeutic or targeted drugs. Recently, we showed that organoid models can also serve as a platform to screen for selectivity and potency of oncolytic adenoviruses (OAds). In this protocol, we describe the steps for tumor organoid adenoviral infection and functional assessment of patient-specific responses to OAds. We provide methods to determine OAd relative efficacy by evaluation of PDO viability after infection and adenoviral replication within cancer cells. For complete details on the use and execution of this protocol, please refer to Raimondi et al. (2020).
| S-EPMC8672098 | biostudies-literature
Project description:Hepatoblastoma, the most prevalent pediatric liver cancer, almost always carries a WNT-activating CTNNB1 mutation, yet exhibits notable molecular heterogeneity. To characterize this heterogeneity and identify novel targeted therapies, we perform comprehensive analysis of hepatoblastomas and tumor-derived organoids using single-cell RNA-seq/ATAC-seq, spatial transcriptomics, and high-throughput drug profiling. We identify two distinct tumor epithelial signatures: hepatic 'fetal' and WNT-high 'embryonal', displaying divergent WNT signaling patterns. The fetal group is enriched for liver-specific WNT targets, while the embryonal group is enriched in canonical WNT target genes. Gene regulatory network analysis reveals enrichment of regulons related to hepatic functions such as bile acid, lipid and xenobiotic metabolism in the fetal subtype but not in the embryonal subtype. In addition, the dichotomous expression pattern of the transcription factors HNF4A and LEF1 allows for a clear distinction between the fetal and embryonal tumor cells. We also perform high-throughput drug screening using patient-derived tumor organoids and identify sensitivity to HDAC inhibitors. Intriguingly, embryonal and fetal tumor organoids are sensitive to FGFR and EGFR inhibitors, respectively, indicating a dependency on EGF/FGF signaling in hepatoblastoma tumorigenesis. In summary, our data uncover the molecular and drug sensitivity landscapes of hepatoblastoma and pave the way for the development of targeted therapies.
| S-EPMC11579375 | biostudies-literature