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The therapeutic effect of KSP inhibitors in preclinical models of cholangiocarcinoma

ABSTRACT: The therapeutic effect of KSP inhibitors in preclinical models of cholangiocarcinoma

PROVIDER: PRJNA874686 | ENA |

REPOSITORIES: ENA

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The therapeutic effect of KSP inhibitors in preclinical models of cholangiocarcinoma

Project description:Cholangiocarcinoma (CCA) is an epithelial malignancy with a dismal prognosis owing to limited treatment options. Here, we identified several compound candidates against CCA using a high-throughput drug screen with approved or emerging oncology drugs, among which kinesin spindle protein (KSP) inhibitors showed potent cytotoxic effects on CCA cells. Treatment with KSP inhibitors SB743921 and ARRY520 caused significant tumor suppression in CCA xenograft models in vivo. Mechanistically, KSP inhibitors led to the formation of abnormal monopolar spindles, which further resulted in the mitotic arrest and cell death of CCA cells both in vivo and in vitro. KEGG pathway analysis of transcriptional data confirmed this finding. Moreover, our clinical data as well as the TCGA database showed KIF11 expression was abundant in most CCA tumor specimens and associated with poor outcomes of CCA patients. Our results demonstrate that the therapeutic regimen of KSP inhibitors could be a promising treatment strategy in CCA.

2022-09-28 | GSE212232 | GEO

Therapeutic efficacy of FASN inhibition in preclinical models of HCC

Project description:Therapeutic efficacy of FASN inhibition in preclinical models of HCC

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Therapeutic efficacy of FASN inhibition in preclinical models of HCC

Project description:Background & Aims: Aberrant activation of fatty acid synthase (FASN) is a major metabolic event during the development of HCC. We evaluated the therapeutic efficacy of TVB3664, a novel FASN inhibitor, either alone or in combination, for HCC treatment. Approach & Results: The therapeutic efficacy and the molecular pathways targeted by TVB3664, either alone or with tyrosine kinase inhibitors or the checkpoint inhibitor anti-PD-L1 antibody, were assessed in human HCC cell lines and multiple oncogene-driven HCC mouse models. RNAseq was performed to characterize the global gene expression and metabolic profiles. TVB3664 effectively ameliorated the fatty liver phenotype in the aged mice and AKT activation-induced hepatic steatosis. TVB3664 monotherapy showed moderate efficacy in NASH-related murine HCCs, induced by loss of PTEN and c-MET overexpression. TVB3664, in combination with cabozantinib, triggered tumor regression in this mouse HCC model but did not improve the responsiveness to immunotherapy. Global gene expression revealed that TVB3664 predominantly modulated metabolic processes, while TVB3664 synergized with cabozantinib to downregulate multiple cancer-related pathways, especially the AKT/mTOR pathway and cell proliferation genes. TVB3664 also improved the therapeutic efficacy of sorafenib and cabozantinib in the FASN-dependent c-MYC HCC model. However, TVB3664 had no efficacy nor synergistic effects in FASN-independent mouse HCC models. Conclusions: This preclinical study suggests the limited efficacy of targeting FASN as monotherapy for HCC treatment. However, FASN inhibitors could be combined with other drugs for improved effectiveness. These combination therapies could be developed based on the driver oncogenes, supporting precision medicine approaches for HCC treatment.

2022-01-28 | GSE189529 | GEO

Development of potent antibody drug conjugates against ICAM1+ cancer cells in preclinical models of cholangiocarcinoma

Project description:Development of potent antibody drug conjugates against ICAM1+ cancer cells in preclinical models of cholangiocarcinoma

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Methylation profiling of preclinical ETMR models

Project description:Methylation profiles of preclinical ETMR models were generated and compared to reference primary human tumors to determine the molecular fidelity of the preclinical model systems.

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Gene expression profiles of IBC (N=10) and nIBC (N=3) cell preclinical models

Project description:Gene expression profiles of 10 IBC preclinical models were analysed to investigate IBC cell intrinsic molecular changes as well as to evaluate to what extent IBC preclinical models recapitulate the IBC expression profile of patient samples.

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Transcription profiling of rat new model of cholangiocarcinoma progression mimicking the human cancer

Project description:Validation of preclinical models of intrahepatic cholangiocarcinoma progression that reliably recapitulate altered molecular features of the human disease would provide an important resource for suggesting and testing of novel target-based therapies against this devastating cancer. In this study, comprehensive gene expression profiling in a novel orthotopic rat model of intrahepatic cholangiocarcinoma progression was carried out in an effort to identify potential therapeutic targets relevant to the progressive human cancer. Microarray analysis was performed on intrahepatic cholangiocarcinomas formed at 10, 15, and 25 days after bile duct inoculation of neu-transformed rat cholangiocytes (BDEneu cells) into rat liver and on peritoneal metastases at the 25 day time period, compared with non-cancerous right liver lobe from the same animals. Experiment Overall Design: Tumors were collected at 10, 15, 25 days post inoculation from biological triplicates (different rats innoculated simultaneously). Also, biological triplicates of metastatic tumors (Mets) at day 25 were analyzed. Biological triplicates of paired normal right liver lobe (RLL) from the same animals from which tumors/mets were obtained were also analyzed in this study. Thus, a total of 9 rats were used for this study.

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