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#hepatocellular carcinoma

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Reproducible safety and efficacy of durvalumab with or without tremelimumab for hepatocellular carcinoma in clinical practice: Results of the DT-real study - PubMed
3 months ago
- Durvalumab plus tremelimumab (STRIDE) is a first-line treatment for unresectable hepatocellular carcinoma (HCC).
- The DT-real study evaluated STRIDE and durvalumab monotherapy in 233 patients across 35 centers, comparing outcomes between those meeting (HIMALAYA-IN) and not meeting (HIMALAYA-OUT) trial criteria.
- Median overall survival (OS) was 20.4 months overall, with HIMALAYA-IN patients achieving significantly longer OS (23.0 months) than HIMALAYA-OUT patients (12.2 months).
- Macrovascular invasion and hepatic decompensation were independent negative prognostic factors, with hepatic decompensation occurring in 10.5% of patients within 12 months.
- Objective response rates were 23.7% for HIMALAYA-IN and 17.8% for HIMALAYA-OUT patients, with disease control linked to improved 24-month OS (58.2% vs. 44.8%).
- Grade 3-4 treatment-related adverse events occurred in 16.3% of patients, showing an acceptable safety profile.
- The study validates STRIDE's efficacy and safety in real-world practice, with hepatic decompensation and disease control as key survival determinants.
Innate lymphoid cell heterogeneity and etiology-specific reprogramming in hepatocellular carcinoma - PubMed
3 months ago
- Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths globally.
- The study profiles innate lymphoid cells (ILCs) in HCC using scRNA-seq, bulk RNA-seq, and CyTOF from 50 patients with different etiologies (HBV and non-viral).
- ILC1 subsets were identified as proliferative (ILC1p) and cytotoxic (ILC1c), while ILC2 showed type-2 immune traits and ILC3 expressed key transcription factors and IL18.
- ILC subsets varied significantly by disease etiology, with NV-HCC ILC2s showing pro-fibrotic and tumor-promoting signatures.
- ILC1s in NV-HCC exhibited activated and cytotoxic phenotypes, whereas HBV-HCC ILC1s showed exhaustion markers like CD96 and TIGIT.
- NV-HCC ILC1s demonstrated enhanced IL-2/IL-15 signaling and interactions with CD8+ T cells via HLA-E, suggesting antitumor potential.
- The study highlights etiology-associated differences in ILC phenotypes and their roles in modulating immune responses in HCC.
Endotrophin and CD44-Mediated Heterotypic Signaling Mediates Tumor-Stroma Crosstalk and Facilitates Malignant Progression in Hepatocellular Carcinoma - PubMed
3 months ago
- Endotrophin (ETP) is a cleavage fragment of collagen VI α3 (COL6A3) and acts as a fibrotic and pro-tumorigenic factor in hepatocellular carcinoma (HCC).
- ETP serves as a diagnostic and prognostic biomarker in HCC, increasing throughout tumor development and promoting progression.
- CD44 was identified as an ETP receptor through peroxidase-catalyzed proximity labeling.
- ETP binding to CD44 activates STAT3 signaling, leading to epithelial-mesenchymal transition (EMT), proliferation, and sorafenib resistance.
- Hepatic stellate cell-derived ETP targets pericentral CD44+ tumor cells, inducing COL6A3 expression and sustaining ETP production via a STAT3-dependent feedback loop.
- Disruption of the ETP-CD44-STAT3 axis by CD44 knockout, STAT3 inhibition, or CD44-binding-deficient ETP mutants suppresses malignant phenotypes in vitro.
- In metabolic dysfunction-associated HCC, dual knockout of Col6a3 and Cd44 in mice reduced tumor burden, restored sorafenib sensitivity, and attenuated EMT, fibrosis, and steatotic-fibrotic niche formation.
- The ETP-CD44-STAT3 axis is a key driver of tumor-stroma crosstalk, linking fibro-inflammation to malignancy, and represents a therapeutic target in obesity-associated liver cancer.
A novel integrative machine learning-based prognostic model reveals lactylation regulation in hepatocellular carcinoma progression - PubMed
3 months ago
- A novel integrative machine learning-based prognostic model, MRLI, was developed for hepatocellular carcinoma (HCC).
- MRLI predicts prognosis and therapeutic outcomes, showing robust predictive capability compared to existing gene signatures.
- Lactylation plays a vital role in metabolic reprogramming and HCC progression, influencing tumor malignancy and immune microenvironment.
- Single-cell and spatial transcriptomics analysis revealed MRLI's association with cellular proliferation and metabolic reprogramming.
- High MRLI correlates with a tumor immunosuppressive microenvironment and decreased sensitivity to treatments like sorafenib and immune checkpoint inhibitors.
- The study suggests lactylation as a potential clinical therapeutic target in HCC.
Development of Novel PROTAC RAD51 Degraders as Enhancers of DNA Damage Response for Hepatocellular Carcinoma Treatment - PubMed
3 months ago
- Development of first-in-class PROTACs targeting RAD51 for hepatocellular carcinoma treatment.
- SZU305 (15b) shows potent RAD51 degradation and antiproliferative effects in liver cancer cell lines.
- Mechanism involves reduced HR efficiency and impaired DNA damage repair, enhancing chemoradiation sensitivity.
- In vivo, SZU305 exhibits strong antitumor activity, especially when combined with sorafenib or irradiation.
- RAD51 degradation presents a novel strategy to overcome drug resistance in liver cancer.
Quality of Gadoxetate-enhanced MRI versus US during Hepatocellular Carcinoma Screening in Participants with Cirrhosis - PubMed
3 months ago
- Gadoxetate-enhanced MRI showed higher quality scores (80.4% MR-A) compared to US (24.2% US-A) in HCC screening for cirrhosis patients.
- Obesity negatively impacted image quality in both MRI and US, though only significant in univariable analysis.
- Child-Pugh B/C scores significantly reduced MRI quality in both univariable and multivariable analyses.
- The study suggests MRI as a more reliable imaging modality for HCC screening in cirrhosis patients, especially where US quality is limited.
Comparative effectiveness of two first-line, ICI-based regimens for advanced HCC: a target trial emulation using an electronic medical record network - PubMed
3 months ago
- Comparative effectiveness of atezolizumab plus bevacizumab (Atezo+Bev) and tremelimumab plus durvalumab (Treme+Dur) as first-line therapies for advanced hepatocellular carcinoma (HCC).
- Study used a target trial emulation approach with real-world data from the TriNetX Research Network, including 640 patients per group after propensity score matching.
- Primary outcome was overall survival (OS), with secondary outcomes including 1- or 2-year OS and immune-related adverse events (irAEs).
- One-year OS was higher in the Atezo+Bev group (61% vs 55%), but two-year OS and overall OS showed no significant differences between the two regimens.
- Hepatic irAEs occurred later in the Atezo+Bev group, while respiratory irAEs appeared earlier in the Treme+Dur group.
- Both regimens demonstrated broadly comparable long-term OS rates, but Treme+Dur may require careful monitoring for early-onset hepatic dysfunction and respiratory irAEs.
Activated ATF6α is a hepatic tumour driver restricting immunosurveillance - PubMed
3 months ago
- Activated ATF6α is identified as a hepatic tumour driver that restricts immunosurveillance in hepatocellular carcinoma (HCC).
- ATF6α activation in human HCC correlates with aggressive tumour phenotypes, reduced patient survival, and local immunosuppression.
- In mice, hepatocyte-specific ATF6α activation leads to progressive hepatitis, ER stress, immunosuppression, and hepatocyte proliferation.
- ATF6α increases glycolysis and directly represses the gluconeogenic enzyme FBP1, contributing to metabolic dysregulation.
- Restoring FBP1 expression can mitigate pathologies associated with ATF6α activation.
- Prolonged ATF6α activation triggers hepatocarcinogenesis and immune exhaustion, which can be reversed by immune checkpoint blockade (ICB).
- Patients with HCC responding well to immunotherapy show increased ATF6α activation.
- Targeting ATF6α through various methods reduces HCC in preclinical models, suggesting it as a therapeutic target.
Extrachromosomal DNA drives molecular and clinical heterogeneity in hepatocellular carcinoma: a multi-omics analysis and prognostic model development - PubMed
3 months ago
- Extrachromosomal DNA (ecDNA) is a key factor in cancer evolution and heterogeneity, particularly in hepatocellular carcinoma (HCC).
- EcDNA-positive HCC tumors exhibit increased vascular invasion, higher AFP levels, and more TP53 mutations.
- These tumors show unique activation of proliferation pathways, decreased stromal infiltration, and heightened immune activation.
- A six-gene signature (RNF186, BMP6, AOC1, FBLL1, MYBL2, DNASE1L3) was developed for prognostic purposes.
- DNASE1L3 was found to be downregulated in HCC and suppresses proliferation and migration of Hep3B2.1-7 cells.
- The study provides insights into ecDNA-driven tumor heterogeneity and offers a prognostic model for personalized HCC management.
Mechanisms of lactylation modification in hepatocellular carcinoma treatment resistance - PubMed
3 months ago
- Hepatocellular carcinoma (HCC) has high global morbidity and mortality, with advanced HCC relying on systemic therapies.
- Primary and acquired drug resistance in HCC severely limits patient survival, necessitating new therapeutic targets.
- Lactylation modification, a novel post-translational modification mediated by lactate, plays a key role in HCC drug resistance.
- Lactylation modifies histones and non-histones, regulating gene expression and contributing to malignant progression and treatment resistance.
- Key resistance mechanisms include lactylated IGF2BP3 activating PCK2-NRF2, ALDOA lactylation enhancing stem cell self-renewal, and MOESIN lactylation in Tregs weakening anti-PD-1 efficacy.
- HCC tissues exhibit higher lactylation levels than normal tissues, correlating with poor prognosis.
- Lactylation-related genes and models can predict treatment responses in HCC.
- Therapeutic strategies like 2-DG, AZD3965, or SIRT3 activators can reverse lactylation and restore drug sensitivity.
- Despite limited specific detectors, lactylation is a promising target to overcome HCC drug resistance and aid precision treatment.
Three-Year Long-Term Outcomes in Patients With Unresectable Hepatocellular Carcinoma Treated With Atezolizumab Plus Bevacizumab Treatment in Clinical Practice - PubMed
3 months ago
- Study evaluates 3-year survival outcomes in unresectable hepatocellular carcinoma (uHCC) patients treated with atezolizumab plus bevacizumab (Atez/Bev) in real-world clinical settings.
- Multicenter retrospective study included 555 patients with Child-Pugh A and BCLC stage B or C, treated from 2020 to 2021.
- Objective response rate (ORR) was 41.3%, disease control rate (DCR) was 79.4%, median progression-free survival (PFS) was 6.2 months, and median overall survival (OS) was 21.6 months.
- 3-year survival rate was 29.7%, with first-line Atez/Bev users showing a higher rate of 35.9%.
- Post-progression treatment was administered to 54.1% of patients, with a median post-progression survival (PPS) of 10.9 months.
- Conversion therapy was performed in 5.9% of patients, and immune-related adverse events (irAEs) occurred in 13.3% (grade 5: 0.7%).
- Findings suggest Atez/Bev provides good ORR, DCR, and favorable long-term survival in uHCC patients.
The use of advanced machine learning to predict outcomes after atezolizumab plus bevacizumab for advanced hepatocellular carcinoma: a retrospective cohort study - PubMed
3 months ago
- Study focused on using advanced machine learning to predict outcomes for advanced hepatocellular carcinoma (HCC) patients treated with atezolizumab plus bevacizumab.
- Retrospective cohort study conducted across 24 centers in eight countries, involving 774 patients after exclusions.
- Seven supervised machine learning models combined with 13 feature selection techniques were trained on 44 baseline clinical variables.
- Ensemble models for overall survival (OS) and progression-free survival (PFS) outperformed traditional clinical benchmarks.
- Patients were stratified into low-risk and high-risk groups, with significant differences in median OS and PFS between groups.
- The study suggests that machine learning models can improve personalized treatment strategies for HCC patients.
Saquinavir induces pyroptosis through the OTUD5-JAK1-GSDME axis in hepatocellular carcinoma - PubMed
3 months ago
- Saquinavir (SAQ) induces pyroptosis in hepatocellular carcinoma (HCC) via the OTUD5-JAK1-GSDME axis.
- SAQ inhibits HCC cell proliferation and triggers caspase-3-GSDME dependent pyroptosis.
- Mechanistically, SAQ blocks glucose metabolism, reduces lactate, and promotes ROS outburst.
- SAQ targets OTUD5, leading to JAK1 degradation, mitochondrial disruption, and pyroptosis activation.
- Combination of SAQ with sorafenib shows synergistic antitumor effects in vitro and in vivo.
- The study highlights SAQ as a novel pyroptosis-inducer and suggests new HCC treatment strategies.
RNF26 regulating tumor immunogenicity of hepatocellular carcinoma by degrading GRP78 and instigating ER stress - PubMed
3 months ago
- RNF26 is highly expressed in immune-'cold' hepatocellular carcinoma (HCC) and is regulated by the JAK-STAT3 inflammatory axis.
- RNF26 degrades the ER chaperone GRP78 via K48-linked polyubiquitination, leading to sustained ER stress in HCC cells.
- ER stress caused by RNF26 results in reduced MHC-I antigen presentation and increased PD-L1 expression, promoting immune evasion.
- RNF26-mediated ER stress inhibits CD8+ T cell infiltration and promotes T cell exhaustion, contributing to immune resistance in HCC.
- Targeting the RNF26-GRP78 axis could be a novel strategy to reverse HCC immune resistance and improve immunotherapy efficacy.
Comparative efficacy of immune checkpoint inhibitor-based regimens versus tyrosine kinase inhibitors in advanced hepatocellular carcinoma stratified by etiology: a systematic review and meta-analysis
2 months ago
- Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality with limited treatment success in advanced stages.
- Tyrosine kinase inhibitors (TKIs) like sorafenib and lenvatinib are first-line treatments but have modest survival benefits and toxicity.
- Immune checkpoint inhibitors (ICIs) show promise, but direct comparisons with TKIs stratified by HCC etiology are lacking.
- A systematic review and meta-analysis compared ICI-based regimens with TKI monotherapies for advanced HCC.
- ICI-based regimens significantly improved overall survival (HR = 0.81) and progression-free survival (HR = 0.76) compared to TKIs.
- ICIs also showed better objective response rate (RR = 1.59) and disease control rate (RR = 1.10) than TKIs.
- ICIs had a lower risk of adverse events of any grade and grades 3-4 compared to TKIs.
- Subgroup analyses revealed significant survival benefits for ICIs in HBV-related HCC (HR = 0.70) but not in HCV-related or non-viral HCC.
- ICI-based therapies provided survival benefits primarily in patients with preserved liver function (CTP A).
- Patients with impaired liver function (CTP B/C) did not receive significant benefits from ICIs.
- ICI-based therapies are more effective and better tolerated than TKI monotherapies, especially in HBV-related HCC and preserved liver function.
WTAP-Mediated Glutaminase Splicing Bias Suppresses Ferroptosis in Hepatocellular Carcinoma - PubMed
2 months ago
- Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with poor prognosis, characterized by hyperactivation of the EGFR signaling pathway.
- Glutaminase (GLS) is commonly overexpressed in malignant tumors, acting as an oncogene to support cell growth and tumor progression.
- The study aimed to understand how EGFR activation drives glutaminolysis reprogramming and confers ferroptosis resistance in HCC.
- AKT, activated by EGFR signaling, phosphorylates WTAP S176, increasing its binding to METTL3, which promotes m6A modification of GLS pre-mRNA.
- This modification favors the alternative splicing of GLS towards GAC over KGA, leading to increased glutamine utilization and glutathione/NADPH biosynthesis.
- The switch to GAC alleviates ferroptosis and promotes tumor growth in mice.
- WTAP pS176 and GAC expression levels are mutually correlated and associated with poor prognosis in HCC patients.
- The findings highlight the therapeutic potential of targeting the m6A-dependent GLS isoform switch in HCC.
Integrative Single-Cell and Spatial Transcriptomic Reveals S100A16+ Tumor Endothelial Cells Drive Angiogenesis and Immunosuppression in Hepatocellular Carcinoma - PubMed
2 months ago
- Identified 6 distinct endothelial cell subpopulations in HCC, with S100A16+ TECs significantly enriched in HCC tissues.
- S100A16+ TECs signature correlates with shorter overall survival and disease-free survival in HCC patients.
- S100A16 overexpression promotes endothelial cell proliferation, migration, and tube formation, driving angiogenesis.
- CCL20 and TGF-β2 identified as key downstream effectors of S100A16+ TECs.
- S100A16+ TECs promote regulatory T cell (Treg) differentiation, contributing to immunosuppression.
- Endothelial-specific S100A16 knockout reduces tumor angiogenesis, Tregs infiltration, and HCC growth in mice.
- High S100A16+ TECs abundance correlates with vascular invasion, immunotherapy resistance, and shorter progression-free survival.
- S100A16+ TECs represent a potential therapeutic target and biomarker for immunotherapy response prediction in HCC.
Microbial metabolites: messengers in the gut-X axis - PubMed
2 months ago
- Microbial metabolites regulate host organ processes.
- Catenibacterium mitsuokai secretes quinolinic acid, activating TIE2/PI3K/AKT pathway in hepatocellular carcinoma.
- Findings provide insights into microbial metabolite-target organ axis.
Transarterial Chemoembolization Combined With Camrelizumab and Rivoceranib for Unresectable Hepatocellular Carcinoma (CHANCE2005/CARES-005): A Randomized Phase II Trial - PubMed
2 months ago
- The study compared TACE combined with camrelizumab and rivoceranib (TACE-C-R) versus TACE alone in unresectable HCC.
- Median progression-free survival (PFS) was significantly longer with TACE-C-R (10.8 months) compared to TACE alone (3.2 months).
- Grade ≥3 treatment-related adverse events were more common with TACE-C-R (74.5%) than with TACE alone (22.3%).
- The most common adverse events were increased AST and ALT levels.
- The combination therapy showed a manageable safety profile and statistically significant improvement in PFS.
Targeting redox metabolism and low-dose radiotherapy synergistically activate cGAS-STING pathway to improve NK cell therapy efficacy in hepatocellular carcinoma - PubMed
2 months ago
- Adoptive NK cell therapy (ANKCT) is a promising treatment for hepatocellular carcinoma (HCC), but its efficacy is limited by insufficient NK cell homing and immunosuppressive M2-polarized tumor-associated macrophages (TAMs).
- Activation of the cGAS-STING pathway enhances NK-cell recruitment and reprograms TAMs toward a proinflammatory M1 phenotype.
- Low-dose radiotherapy (LDRT) activates the cGAS-STING pathway via ROS-mediated DNA damage but is hindered by HCC's robust antioxidant systems (Trx and GSH).
- A biomimetic nanoparticle (A@MMOF) was developed to disrupt tumor redox homeostasis by inhibiting GSH and Trx, amplifying ROS levels, and synergizing with LDRT to activate the cGAS-STING pathway.
- A@MMOF combined with LDRT remodels the tumor microenvironment, enhances NK cell infiltration and activation, and improves ANKCT efficacy in HCC.

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#hepatocellular carcinoma

Reproducible safety and efficacy of durvalumab with or without tremelimumab for hepatocellular carcinoma in clinical practice: Results of the DT-real study - PubMed

Innate lymphoid cell heterogeneity and etiology-specific reprogramming in hepatocellular carcinoma - PubMed

Endotrophin and CD44-Mediated Heterotypic Signaling Mediates Tumor-Stroma Crosstalk and Facilitates Malignant Progression in Hepatocellular Carcinoma - PubMed

A novel integrative machine learning-based prognostic model reveals lactylation regulation in hepatocellular carcinoma progression - PubMed

Development of Novel PROTAC RAD51 Degraders as Enhancers of DNA Damage Response for Hepatocellular Carcinoma Treatment - PubMed

Quality of Gadoxetate-enhanced MRI versus US during Hepatocellular Carcinoma Screening in Participants with Cirrhosis - PubMed

Comparative effectiveness of two first-line, ICI-based regimens for advanced HCC: a target trial emulation using an electronic medical record network - PubMed

Activated ATF6α is a hepatic tumour driver restricting immunosurveillance - PubMed

Extrachromosomal DNA drives molecular and clinical heterogeneity in hepatocellular carcinoma: a multi-omics analysis and prognostic model development - PubMed

Mechanisms of lactylation modification in hepatocellular carcinoma treatment resistance - PubMed

Three-Year Long-Term Outcomes in Patients With Unresectable Hepatocellular Carcinoma Treated With Atezolizumab Plus Bevacizumab Treatment in Clinical Practice - PubMed

The use of advanced machine learning to predict outcomes after atezolizumab plus bevacizumab for advanced hepatocellular carcinoma: a retrospective cohort study - PubMed

Saquinavir induces pyroptosis through the OTUD5-JAK1-GSDME axis in hepatocellular carcinoma - PubMed

RNF26 regulating tumor immunogenicity of hepatocellular carcinoma by degrading GRP78 and instigating ER stress - PubMed

Comparative efficacy of immune checkpoint inhibitor-based regimens versus tyrosine kinase inhibitors in advanced hepatocellular carcinoma stratified by etiology: a systematic review and meta-analysis

WTAP-Mediated Glutaminase Splicing Bias Suppresses Ferroptosis in Hepatocellular Carcinoma - PubMed

Integrative Single-Cell and Spatial Transcriptomic Reveals S100A16+ Tumor Endothelial Cells Drive Angiogenesis and Immunosuppression in Hepatocellular Carcinoma - PubMed

Microbial metabolites: messengers in the gut-X axis - PubMed

Transarterial Chemoembolization Combined With Camrelizumab and Rivoceranib for Unresectable Hepatocellular Carcinoma (CHANCE2005/CARES-005): A Randomized Phase II Trial - PubMed

Targeting redox metabolism and low-dose radiotherapy synergistically activate cGAS-STING pathway to improve NK cell therapy efficacy in hepatocellular carcinoma - PubMed