Expression data for iPSC-derived hepatocyte-like cells (HLCs) treated with 100 µM pazopanib for 24 hours
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE75888 | GEO | 2016/09/30
SECONDARY ACCESSION(S): PRJNA305614
REPOSITORIES: GEO
Similar Datasets
Project description:Interindividual differences in hepatic metabolism, which are mainly due to genetic polymorphism in its gene, have a large influence on individual drug efficacy and adverse reaction. Hepatocyte-like cells (HLCs) differentiated from human induced pluripotent stem (iPS) cells have the potential to predict interindividual differences in drug metabolism capacity and drug response. However, it remains uncertain whether human iPSC-derived HLCs can reproduce the interindividual difference in hepatic metabolism and drug response. We found that cytochrome P450 (CYP) metabolism capacity and drug responsiveness of the primary human hepatocytes (PHH)-iPSHLCs were highly correlated with those of PHHs, suggesting that the PHH-iPS-HLCs retained donor-specific CYP metabolism capacity and drug responsiveness. We also demonstrated that the interindividual differences, which are due to the diversity of individual SNPs in the CYP gene, could also be reproduced in PHH-iPS-HLCs. We succeeded in establishing, to our knowledge, the first PHH-iPS-HLC panel that reflects the interindividual differences of hepatic drugmetabolizing capacity and drug responsiveness.
2014-11-12 | GSE61287 | GEO
Project description:Acquired drug resistance and tumour relapse impacts the majority of patients being treated with tyrosine kinase inhibitors (TKIs) and remains a key challenge in modern anti-cancer therapy. The lack of clinically effective therapeutic strategies to overcome drug resistance represents a significant unmet need. Understanding the signalling pathways that drive drug resistance will facilitate the development of new salvage therapies to effectively treat patients with secondary TKI resistance. In this study, we utilise quantitative mass spectrometry to characterise the global phosphoproteomic alterations that accompany the acquisition of resistance to two FDA-approved multi-target TKIs, pazopanib and dasatinib, in the A204 rhabdoid tumour cell line. Our analysis finds that only a limited fraction of the quantified phosphoproteome (<10%) is altered upon the acquisition of drug resistance with pazopanib resistant cells displaying elevated phosphorylation levels in cytoskeletal regulatory pathways and dasatinib resistant cells showing an upregulation of components of the insulin receptor/IGF1-R signalling pathway. Drug response profiling with a targeted panel of small molecule inhibitors rediscovers several previously reported vulnerabilities associated with pazopanib and dasatinib resistance and identifies a new dependency to the second generation HSP90 inhibitor NVP-AUY-922. This study provides a useful resource detailing the candidate signalling determinants of acquired TKI resistance; and reveals a therapeutic approach of inhibiting HSP90 function as a means of salvage therapy to overcome pazopanib and dasatinib resistance.
2017-08-30 | PXD005536 | Pride
Project description:Dermatofibrosarcoma protuberans (DFSP) is a soft-tissue sarcoma characterized by a high risk of local infiltration. The identification of the COL1A1-PDGFB t(17;22) translocation activating the PDGF pathway led to the use of imatinib in unresectable DFSP, with a response rate of 36-80%. Pazopanib is a multitarget tyrosine kinase inhibitor approved for soft tissue sarcomas. We conducted a phase II study of patients with unresectable DFSP to evaluate the efficacy and safety of pazopanib. Patients received 800 mg pazopanib daily. The primary endpoint was the objective response rate defined as the reduction of the largest diameter of the tumor ≥30% at 6 months or at surgery assessed by physical examination. Twenty-three patients, including one pre-treated with imatinib, were enrolled. With a median follow-up of 6.2 months (interquartile range 5.6-7.8 months), 5 patients (22%, 95% CI: 7-22%) had a partial response to pazopanib. The best objective response rate was 30% (95% CI 13-53%) using RECIST. One patient with metastatic DFSP previously treated with imatinib died after 2.4 months. Nine (39%) patients discontinued the treatment due to adverse events. Pharmacodynamics analyses of tumor samples were conducted: the enrichment of EGF and the EGFR-associated gene panel was associated with resistance, suggesting that EGFR-targeted therapies could be a therapeutic option to explore in DFSP.
2020-05-19 | GSE150787 | GEO
Project description:In drug development, a system for predicting drug metabolism and drug-induced toxicity is necessary to ensure drug safety. Cytochrome P450 family 3 subfamily A member 4 (CYP3A4) is an important drug-metabolizing enzyme expressed in the liver and small intestine, and predicting CYP3A4-mediated drug metabolism and drug-induced toxicity is essential. We previously developed procedures to differentiate human induced pluripotent stem (iPS) cells into hepatocyte-like cells (HLCs) or intestinal epithelial-like cells (IECs) with a fetal phenotype as well as a highly efficient genome editing technology that could enhance the homologous recombination efficiency at any locus, including CYP3A4. By using human iPS cells and our genome editing technology, we generated CYP3A4-knockout (KO) iPS cell-derived HLCs and IECs for the evaluation of CYP3A4-mediated drug metabolism and drug-induced toxicity. CYP3A4 deficiency did not affect pluripotency and hepatic and intestinal differentiation capacities, and CYP3A4 activity was entirely eradicated by CYP3A4 KO. Off-target effects (e.g., inhibition of bile acid excretion) were hardly observed in CYP3A4-KO cells but were observed in CYP3A4 inhibitor-treated (e.g., ketoconazole) cells. To evaluate whether drug-induced hepatotoxicity and enterotoxicity could be predicted using our model, we exposed CYP3A4-KO HLCs and IECs to acetaminophen, amiodarone, desipramine, leflunomide, tacrine, and tolcapone and confirmed that these cells could predict CYP3A4-mediated toxicity. Finally, we examined whether the therapeutic effects of an anti-hepatitis C virus (HCV) drug metabolized by CYP3A4 would be predicted using our model. CYP3A4-KO HLCs were treated with asunaprevir (antiviral drug metabolized by CYP3A4) after HCV infection, and the anti-viral effect was indeed strengthened by CYP3A4 KO. Conclusion: We succeeded in generating a novel evaluation system for prediction of CYP3A4-mediated drug metabolism and drug-induced toxicity.
2021-05-06 | GSE159159 | GEO
Project description:The purpose of this experiment was to compared the transcriptome of hepatocyte-like cells (HLCs) generated in vitro and adult primary human hepatocytes (PHHs). HLCs were differentiated from either hESCs or hIPSCs using previously established protocols (Hannah et al 2013; Segeritz et al 2018). Undifferentiated hIPSCs were used as control to confirm differentiation status. PHHs were commercially sourced as well as freshly isolated from donors.
2022-08-11 | E-MTAB-10634 | biostudies-arrayexpress
Project description:Bone and soft tissue sarcomas are rare and highly heterogeneous mesenchymal malignancies. Their rarity makes it difficult to acquire clinical data of patients with specific histological subtypes of sarcoma from large clinical trials. The diagnoses and treatment of sarcomas need to be further developed. We show that a long non-coding RNA (lncRNA) HAR1B may serve as predictive biomarkers for pazopanib treatment in bone and soft tissue sarcomas. Multiplex real-time reverse transcription polymerase chain reaction and microarray analyses revealed that HAR1B and HOTAIR were differentially expressed in pazopanib-sensitive cells and responders. We further clarified this mechanism by showing that siRNA-knockdown of HAR1B led to an increased resistance to pazopanib in sarcoma cell lines. Gene expression profiles related to pazopanib sensitivity included cellular molecular pathways, including genes involved in von-Willebrand factor-related signaling. Our study demonstrates that lncRNA HAR1B expression affects cellular sensitivity to pazopanib in sarcoma cell lines and in patients with sarcoma.
2021-04-28 | GSE156344 | GEO
Project description:Background: The sequential and combination treatment with immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) in metastatic renal cell carcinoma (mRCC) patients has entered the clinical practice. The dissection of the molecular mechanisms governing the impact of TKIs on the immune system is critical to implement therapeutic approaches and generate biomarkers. We here investigated the immunomodulatory activity of pazopanib in peripheral blood mononuclear cells (PBMCs) of mRCC patients through an integrative genomic analysis pipeline. Results: The transcriptional analysis indicates a modulation of leukocyte functional orientation induced by pazopanib with an increase of immune effector cell subtypes and a decrease of immune suppressive populations. At the group level transcriptome profiles revealed perturbations to peak at 3 and decrease at 6 months. These included enrichments of modules associated with cytotoxic/NK (M3.6 and M8.46), plasma cells (M4.11), T cell (M4.15) and immune responses (M8.89). At individual patient level, pazopanib administration was associated with a decrease of the immunosuppressive module M9.34 in the majority of patients. Interestingly, a rapid increase of Interferon (IFN) modules (M1.2 and M3.4) was observed exclusively in patients displaying a strong enrichment in modules associated with cytotoxic/NK cells. Multicolor flow cytometry confirmed the association of pazopanib treatment with a decrease of immune suppressive cell subsets, including CD14+HLA-DRneg myeloid derived suppressor cells (MDSCs), CD14+ and CD14+PD-L1+ monocytes, CD15+ granulocytic MDSCs and CD4+CD25highFoxp3+ regulatory T cells. Concomitantly, a boost of activated CD3+PD-1dim T lymphocytes and cytotoxic CD3-CD16+CD56dim NK cells was observed. These changes were predominantly detectable after 3 months of therapy with pazopanib. Conclusions: As systems approach, pazopanib reshapes anti-tumor immunity by relieving immunosuppression and triggering cytotoxic mechanisms and IFN pathways. The peak of this immune modulation is observed after 3 months of therapy. Our data provides a strong rationale in support of combinatorial or sequential therapies based on TKIs and immunotherapy approaches and for implementing transcriptomic analysis of blood as biomarker of immune responses.
2021-06-28 | GSE146163 | GEO
Project description:ChIP-sequencing was performed to explore the difference between the epigenetic profiles of hepatocyte-like cells (HLCs) generated in vitro and primary human hepatocytes (PHHs). HLCs were differentiated from hIPSCs and hESCs for 30 days, as previously reported (Hannan et al, 2013). PHHs were purchased from Biopredic. Chromatin was immunoprecipitated with antibodies against H3K27ac, H3K4me1, H3K27me3 and H3K4me3. Library preparation and sequencing were performed by the Wellcome Trust Sanger Institute DNA Sequencing Facility (Hinxton, UK). Sequencing was performed on an Illumina HiSeq v4 instrument to obtain paired-end reads with 75bp length.
2022-08-11 | E-MTAB-10637 | biostudies-arrayexpress
Project description:We investigated the transcriptome of human induced pluripotent stem cells (hiPSCs) differentiated into hepatocyte-like cells (HLCs) in a biochip culture environment vs. standard Petri dishes cultures using nanoCAGE, a method for promoters, transcription factors, and transcriptome analysis.
2020-12-01 | GSE149806 | GEO
Project description:The aim of the experiment was to discover differentially expressed miRNAs correlating with prolonged response to targeted therapy in patients with metastatic renal cell carcinoma treated with sunitinib or pazopanib
2018-02-08 | E-MTAB-6296 | biostudies-arrayexpress