Therapeutic efficacy of FASN inhibition in preclinical models of HCC
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA783327 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17031700_1.fastq.gz | Fastqsanger.gz | |||
| SRR17031700_2.fastq.gz | Fastqsanger.gz | |||
| SRR17031701_1.fastq.gz | Fastqsanger.gz | |||
| SRR17031701_2.fastq.gz | Fastqsanger.gz | |||
| SRR17031702_1.fastq.gz | Fastqsanger.gz |
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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
Project description:We have generated a collection of patient-derived xenograft (PDX) tumor models and characterized them at the molecular level to facilitate precision oncology. Surgically resected HCC specimens were subcutaneously implanted in immunodeficient mice. Resulting xenografts were serially implanted to establish transplantable PDX models, which were sequentially subject to whole exome sequencing (WES), gene expression array, genome-wide human single nucleotide polymorphism (SNP) array 6.0, and serum a–fetoprotein (AFP) detection assay. The feasibility as a preclinical model was validated by efficacy studies using a standard-of-care (SOC) and a targeted agent, respectively.
2014-03-13 | E-GEOD-55828 | biostudies-arrayexpress
Project description:Hepatocellular carcinoma (HCC) currently lacks effective therapies, leaving a critical need for new treatment options. A previous study identified the Anaplastic Lymphoma Kinase (ALK) amplification in HCC patients, raising the question of whether ALK inhibitors could be a viable treatment. Here, we showed that both ALK inhibitors and ALK knockout effectively halted HCC growth in cell cultures. Lorlatinib, a potent ALK inhibitor, suppressed HCC tumor growth and metastasis across various mouse models. Additionally, in an advanced immunocompetent humanized mouse model, when combined with an anti-PD-1 antibody, lorlatinib more potently suppressed HCC tumor growth, surpassing individual drug efficacy. Lorlatinib induced apoptosis and senescence in HCC cells, and the senolytic agent ABT-263 enhanced the efficacy of lorlatinib. Additional studies identified that the apoptosis-inducing effect of lorlatinib was mediated via GGN and NRG4. These findings establish ALK inhibitors as promising HCC treatments, either alone or in combination with immunotherapies or senolytic agents.
2024-04-29 | GSE178211 | GEO
Project description:Background & Aims: Immune checkpoint inhibitors combined with anti-angiogenic agents produces benefits in the treatment of advanced hepatocellular carcinoma (HCC). We investigated the efficacy and immunomodulatory activity of cabozantinib alone and combined with anti-PD1 in experimental models of HCC, and explored the potential target population that might benefit from this combination. Approach & Results: C57BL/6J mice bearing subcutaneous Hepa1-6 or Hep53.4 tumours received cabozantinib, anti-PD1, their combination or placebo. Tumour and blood samples were analysed by flow cytometry, immunohistochemistry, transcriptome and cytokine profiling. Cabozantinib-related effects were validated in a colorectal cancer PDX model. Transcriptomic data from three human HCC cohorts (Cohort 1: n=167, Cohort 2: n=57, TCGA: n=319) were used to cluster patients according to neutrophil features, and assess their impact on survival. The combination of cabozantinib and anti-PD1 showed increased anti-tumour efficacy compared to monotherapy and placebo (P<0.05). Cabozantinib alone significantly increased neutrophil infiltration and reduced CD8+PD1+ T cell proportions in the tumour, while the combination with anti-PD1 further stimulated both effects and significantly decreased T regulatory cell infiltration (all P<0.05). In blood, cabozantinib and especially combination increased the proportions of overall T cells (P<0.01) and memory/effector T cells (P<0.05), while lowering the neutrophil-to-lymphocyte ratio (P<0.001 for combination). Unsupervised clustering of human HCCs revealed that high tumour enrichment in neutrophil features observed with the treatment combination was linked to less proliferative phenotypes, and well-differentiated HCC with better prognosis. Neutrophil recruitment in both humans and mice was linked to CXCR2 ligands and CXCL12 (P<0.05). Conclusions: Cabozantinib in combination with anti-PD1 enhanced anti-tumour immunity by bringing together innate neutrophil-driven and adaptive immune responses, a mechanism of action which favours this approach for the treatment of HCC.
2022-06-15 | GSE174570 | GEO
Project description:Exercise inhibits tumor progression and improves the therapeutic efficacy of PD-1 blockade in colorectal cancer preclinical models
| PRJNA722267 | ENA
Project description:Background & Aims: Immune checkpoint inhibitors combined with anti-angiogenic agents produces benefits in the treatment of advanced hepatocellular carcinoma (HCC). We investigated the efficacy and immunomodulatory activity of cabozantinib alone and combined with anti-PD1 in experimental models of HCC, and explored the potential target population that might benefit from this combination. Approach & Results: C57BL/6J mice bearing subcutaneous Hepa1-6 or Hep53.4 tumours received cabozantinib, anti-PD1, their combination or placebo. Tumour and blood samples were analysed by flow cytometry, immunohistochemistry, transcriptome and cytokine profiling. Cabozantinib-related effects were validated in a colorectal cancer PDX model. Transcriptomic data from three human HCC cohorts (Cohort 1: n=167, Cohort 2: n=57, TCGA: n=319) were used to cluster patients according to neutrophil features, and assess their impact on survival. The combination of cabozantinib and anti-PD1 showed increased anti-tumour efficacy compared to monotherapy and placebo (P<0.05). Cabozantinib alone significantly increased neutrophil infiltration and reduced CD8+PD1+ T cell proportions in the tumour, while the combination with anti-PD1 further stimulated both effects and significantly decreased T regulatory cell infiltration (all P<0.05). In blood, cabozantinib and especially combination increased the proportions of overall T cells (P<0.01) and memory/effector T cells (P<0.05), while lowering the neutrophil-to-lymphocyte ratio (P<0.001 for combination). Unsupervised clustering of human HCCs revealed that high tumour enrichment in neutrophil features observed with the treatment combination was linked to less proliferative phenotypes, and well-differentiated HCC with better prognosis. Neutrophil recruitment in both humans and mice was linked to CXCR2 ligands and CXCL12 (P<0.05). Conclusions: Cabozantinib in combination with anti-PD1 enhanced anti-tumour immunity by bringing together innate neutrophil-driven and adaptive immune responses, a mechanism of action which favours this approach for the treatment of HCC.
2022-06-15 | GSE174770 | GEO
Project description:Preclinical efficacy of the MTH1 inhibitor karonudib in B-cell lymphoma
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Project description:Exercise training (ExT) has shown antitumor effects in many preclinical cancer models. In the present study, we utilize MC38 and CT26 cells, which represent MSI and MSS colorectal carcinomas respectively, to study the effects and mechanisms of ExT alone or in combination with PD-1 based immunotherapy. Using treadmill running and PD-1/PD-L1 blockade, we demonstrated that post-implant exercise training has broad anticancer activities in murine models of CRC. Specifically, in MSI CRC models, ExT induces beneficial metabolic and immunological adaptations, leading to a more significant inhibition in tumors treated with PD-1/PD-L1 blockade, suggesting a genotype-directed combinatory therapy for the subgroup of CRC patients. Moreover, ExT might be a safe and alternative anticancer strategy for cancers resistant to the PD-1 based immunotherapy, such as patients with MSS CRC tumors.
2021-04-16 | GSE172162 | GEO
Project description:We examined FASN knockdown LNCaP cells obtained by shRNA transduction with Mission lentiviral transduction particles (SHCLNV-NM 00410, TRCN3128, Sigma) (FASN-RNAi cells). In this study, we used cells transfected with non-targeting shRNA as a control (control-RNAi cells). The expression of genes related to cellular proliferation (phospholipase A2, group IVA, PLA2G4A; tensin 3, TNS3; glypican 4 GPC4), cell adhesion and extracellular matrix organization [peroxidasin homolog (Drosophila) PXDN; sarcoglycan epsilon, SGCE; von Willebrand factor, VWF; hydroxysteroid (17-beta) dehydrogenase 12, HSD17B12; cysteine-rich secretory protein LCCL domain containing 2, CRISPLD2], and cell motility (TNS3, RAP2B member of RAS oncogene family, RAP2B) were shown to be down-regulated by FASN inhibition with RNAi. FASN inhibition led to down-regulation of the PLA2G4A and HSD17B12 genes encoding phospholipase A2 and 17-beta hydroxysteroid dehydrogenase, respectively, which are the key enzymes related to production of an intracellular second messenger arachidonic acid and androgen hormones, both playing roles in promotion of tumor progression. We also found that the genes related to arachidonic acid signalling, including RGS2, SPAG16, VWF and RAP2B, were also suppressed with FASN inhibition. Gene expression profiling therefore demonstrated that FASN inhibition induces down-regulation of genes related to cell proliferation, cell adhesion, migration, and invasion, as well as the production of arachidonic acid and androgen hormones, both of which drive tumor progression. Total RNA isolation was performed with a Micro-to-Midi total RNA purification system (Invitrogen). The integrity of total RNAs was evaluated using an Agilent 2100 Bioanalyzer (Agilent Technologies). Low Input Quick Amp Labeling Kit, one-color (Agilent Technologies) was used to prepare Cy3-labelled target cRNA according to the manufacturer's instructions. Labeled cRNAs were hybridized with a SurePrint G3 Human GE 8M-CM-^W60K Microarrays (Agilent Technologies). Two separate hybridizations were performed for each sample. Array images were captured using a DNA Microarray Scanner (Agilent Technologies), and data were analyzed using Feature Extraction Software (Agilent Technologies) to obtain background-corrected signal intensities. The data were further analysed with GeneSpring GX Software (Version 11.0, Agilent Technologies). After filtering of data, mRNAs differentially expressed in target versus control were considered using the Fisher exact test, followed by multiple corrections using the Benjamini and Hochberg false discovery rate (FDR) method. Gene sets with a FDR q-value < 0.05 were considered significant.
2012-07-09 | E-GEOD-39183 | biostudies-arrayexpress
Project description:The fatty acid synthase (FASN) is the major fat synthesizing enzyme. FASN is an indispensable enzyme because mice with genetic deletion of Fasn are not viable. Apart from its physiological function, previous studies indicated that FASN could also exert a pathophysiological role, in the heart, because patients with heart failure showed up-reguation of FASN. To investigate the in vivo function of FASN up-regulation in the heart, we generated mice with myocardium-specific expression of FASN under control of the alpha-MHC promoter. Two different founder lines were generated with high and low FASN over-expression. Microarray gene expression profiling of heart tissue was performed of heart tissue from transgenic mice with high and low FASN expression Microarray gene expression profiling was performed with heart tissue isolated from three study groups: (i) Transgenic mice with high cardiac FASN expression, (ii) transgenic mice with low cardiac FASN expression, and (iii) B6 control mice.
2013-07-31 | E-GEOD-49351 | biostudies-arrayexpress