Toripalimab combined with lenvatinib and GEMOX is a promising regimen as first-line treatment for advanced intrahepatic cholangiocarcinoma: a single-center, single-arm, phase 2 study

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: March 17, 2023

Abstract Advanced intrahepatic cholangiocarcinoma (ICC) has a dismal prognosis. Here, we report the efficacy and safety of combining toripalimab, lenvatinib, gemcitabine plus oxaliplatin (GEMOX) as first-line therapy for advanced ICC. Thirty patients with pathologically confirmed ICC received intravenous (1 g/m 2 ) on Days 1 8 (85 mg/m Q3W six cycles along toripalimab (240 mg) oral lenvatinib (8 once daily one year. The expression programmed death-ligand (PD-L1) genetic status was investigated in paraffin-embedded tissues using immunohistochemistry whole-exome sequencing (WES) analysis. primary endpoint objective response rate (ORR). Secondary outcomes included safety, overall survival (OS), progression-free (PFS), disease control (DCR) duration (DoR). As July 1, 2022, median follow-up time 23.5 months, ORR 80%. Twenty-three achieved partial response, complete response. Patients (21/30) DNA damage (DDR)-related gene mutations showed higher ORR, while (14/30) tumor area positivity ≥1 (PD-L1 staining) trend high but without significant difference. OS, PFS, DoR were 22.5, 10.2, 11.0 respectively. DCR 93.3%. Further, 56.7% experienced manageable grade ≥3 adverse events (AEs), commonly neutropenia (40.0%) leukocytopenia (23.3%). In conclusion, GEMOX are promising regimens treatment A phase-III, multicenter, double-blinded, randomized study to validate our findings approved by National Medical Products Administration (NMPA, No. 2021LP01825). Trial registration Clinical trials : NCT03951597.

Language: Английский

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Nucleolin lactylation contributes to intrahepatic cholangiocarcinoma pathogenesis via RNA splicing regulation of MADD

Journal of Hepatology, Journal Year: 2024, Volume and Issue: unknown

Published: April 1, 2024

Intrahepatic cholangiocarcinoma (iCCA) is a fatal malignancy of the biliary system. The lack detailed understanding oncogenic signaling or global gene expression alterations has impeded clinical iCCA diagnosis and therapy. role protein lactylation, newly unraveled post-translational modification that orchestrates expression, remains largely elusive in pathogenesis iCCA.

Language: Английский

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Establishment and characterization of three gemcitabine-resistant human intrahepatic cholangiocarcinoma cell lines

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: Feb. 9, 2025

Intrahepatic cholangiocarcinoma (ICC) is a highly malignant liver tumor associated with dismal prognosis, largely due to chemotherapy resistance. However, the mechanisms underlying gemcitabine (GEM) resistance in ICC remain poorly understood. In this study, we established three GEM-resistant cell models and evaluated their by assessing proliferation, cycle arrest, DNA damage. cells exhibited significant tolerance GEM-induced growth inhibition, reduced decreased damage compared parental cells. We then explored potential found that pathways targets such as epithelial-mesenchymal transition, PI3K/Akt, p53R2, IGF-1R did not show correlation Interestingly, our findings suggested reactive oxygen species might promote GEM ICC. conclusion, characterized model, which can be employed investigate alternative explore new treatment approaches.

Language: Английский

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Long-Term Outcomes According to Surgical Margin in Mass-Forming Cholangiocarcinoma: The Role of R1vasc

Annals of Surgical Oncology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 28, 2025

Language: Английский

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Tumor-derived exosomal LINC01812 induces M2 macrophage polarization to promote perineural invasion in cholangiocarcinoma

Cancer Letters, Journal Year: 2025, Volume and Issue: 617, P. 217596 - 217596

Published: March 12, 2025

M2 macrophages play a critical role in the tumor microenvironment of invasive solid tumors. They are closely associated with perineural invasion (PNI) and often linked to poor prognosis. In this context, tumor-derived exosomes serve as important mediators intercellular communication. However, relationship between cell-induced PNI cholangiocarcinoma remains unexplored. study, we utilized multiplex immunofluorescence transcriptomic sequencing demonstrate upregulation LINC01812 tissues its positive correlation macrophage infiltration. Exosomal lncRNA sequencing, exosome uptake experiments, RNA pull-down assays, mass spectrometry analysis demonstrated that can internalize exosomal promote phenotype cells. Additionally, Transwell vitro cocultures dorsal root ganglia confirmed significantly enhances nerve infiltration cells via macrophages. The findings study indicate containing derived from induce polarization facilitate infiltration, thereby providing new potential therapeutic targets for managing cholangiocarcinoma.

Language: Английский

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FASN-mediated fatty acid biosynthesis remodels immune environment in Clonorchis sinensis infection-related intrahepatic cholangiocarcinoma

Journal of Hepatology, Journal Year: 2024, Volume and Issue: 81(2), P. 265 - 277

Published: March 19, 2024

Language: Английский

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Microwave ablation versus liver resection for primary intrahepatic cholangiocarcinoma within Milan criteria: a long-term multicenter cohort study

EClinicalMedicine, Journal Year: 2024, Volume and Issue: 67, P. 102336 - 102336

Published: Jan. 1, 2024

BackgroundAblation has been recommended by worldwide guidelines as first-line treatment for hepatocellular carcinoma (HCC), while evidence regarding its efficacy primary intrahepatic cholangiocarcinoma (iCCA) is lacking. We aimed to study the of ablation in treating iCCA comparing prognosis with surgery.MethodsIn this real-world multicenter cohort from January 2009 June 2022, 10,441 patients ten tertiary hospitals were identified. Patients who underwent curative-intent microwave (MWA) or liver resection (LR) tumors within Milan criteria included. One-to-many propensity score matching (PSM) at variable ratios (1:n ≤4) was used balance baseline characteristics. Mediation analysis applied identify potential mediators survival difference.Findings944 finally enrolled study, 221 undergoing MWA and 723 LR. After PSM, 203 group matched 588 LR group. The median follow-up time 4.7 years. Compared LR, demonstrated similar overall (5-year 44.8% versus 40.4%; HR 0.96, 95% CI 0.71–1.29, P = .761). There an improvement 5-year disease-free rate 17.1% during period 2009–2016 37.3% 2017–2022, becoming comparable 40.8% (P .129). proportion ablative margins ≥5 mm increased 25% 61% over two periods, surgical 62% 77%, respectively. 34.5% DFS disparity can be explained mediation effect < .0001). Similar observed when both exceeded 5 (HR 0.83, 0.52–1.32, .41).InterpretationMWA may considered a viable alternative adequate margin obtained.FundingNational Natural Science Foundation China.

Language: Английский

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Intrahepatic cholangiocarcinoma biomarkers: Towards early detection and personalized pharmacological treatments

Molecular and Cellular Probes, Journal Year: 2024, Volume and Issue: 73, P. 101951 - 101951

Published: Jan. 20, 2024

Language: Английский

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USP21 deubiquitinates and stabilizes HSP90 and ENO1 to promote aerobic glycolysis and proliferation in cholangiocarcinoma

International Journal of Biological Sciences, Journal Year: 2024, Volume and Issue: 20(4), P. 1492 - 1508

Published: Jan. 1, 2024

Deubiquitylating enzymes (DUBs) play an essential role in targeted protein degradation and represent emerging therapeutic paradigm cancer.However, their potential cholangiocarcinoma (CCA) has not been explored.Herein, based on The Cancer Genome Atlas (TCGA) Gene Expression Omnibus (GEO) databases, we found that ubiquitin-specific protease 21 (USP21) was upregulated CCA, high USP21 level associated with poor prognosis.In vivo vitro, identified as a master regulator of CCA growth maintenance, which directly interacted deubiquitinates stabilized the heat shock 90 (HSP90) through K48-linked deubiquitination, turn, this stabilization increased HIF1A expression, thus upregulating key glycolytic enzyme genes ENO2, ENO3, ALDOC, ACSS2, then promoted aerobic glycolysis, provided energy for cell proliferation.In addition, could stabilize alpha-Enolase 1 (ENO1) to promote glycolysis.Furthermore, enhanced chemotherapy resistance gemcitabine-based regimen.Taken together, identify USP21-regulated glycolysis mechanism involves USP21/HSP90/HIF1A axis USP21/ENO1 tumorigenesis, serve target treatment CCA.

Language: Английский

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Doxycycline Restores Gemcitabine Sensitivity in Preclinical Models of Multidrug-Resistant Intrahepatic Cholangiocarcinoma

Cancers, Journal Year: 2025, Volume and Issue: 17(1), P. 132 - 132

Published: Jan. 3, 2025

Background/Objectives: Intrahepatic cholangiocarcinoma (iCCA) is a malignant liver tumor with rising global incidence and poor prognosis, largely due to late-stage diagnosis limited effective treatment options. Standard chemotherapy regimens, including cisplatin gemcitabine, often fail because of the development multidrug resistance (MDR), leaving patients few alternative therapies. Doxycycline, tetracycline antibiotic, has demonstrated antitumor effects across various cancers, influencing cancer cell viability, apoptosis, stemness. Based on these properties, we investigated potential doxycycline overcome gemcitabine in iCCA. Methods: We evaluated efficacy two MDR iCCA lines, MT-CHC01R1.5 82.3, assessing cycle perturbation, apoptosis induction, stem compartment impairment. assessed vivo combining mouse xenograft models. Results: Treatment both lines resulted significant reduction viability (IC50 ~15 µg/mL) induction apoptosis. Doxycycline also diminished population, as indicated by reduced cholangiosphere formation. In studies showed that while neither nor alone significantly growth, their combination led marked decreases volume weight at study endpoint. Additionally, metabolic analysis revealed glucose uptake tumors, monotherapy more effectively gemcitabine. Conclusions: These findings suggest doxycycline, especially can restore sensitivity iCCA, providing promising new strategy for improving outcomes this challenging disease.

Language: Английский

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