RARE DISEASE
Carcinoma of gallbladder and extrahepatic biliary tract
Carcinoma of gallbladder and extrahepatic biliary tract
Carcinoma of gallbladder and extrahepatic biliary tract
Synonyms: Carcinoma of gallbladder and EBT
Synonyms: Carcinoma of gallbladder and EBT
Synonyms: Carcinoma of gallbladder and EBT
Drug discovery
32
drugs
With orphan designations
Overview
Carcinoma of the gallbladder (GBC) and extrahepatic biliary tract (e.g., cholangiocarcinoma) are aggressive malignancies often diagnosed at advanced stages due to nonspecific symptoms. GBC is strongly linked to gallstones (>70% of cases [1][5][12]), female sex, and geographic variations (e.g., high incidence in South America and Asia) [5][13]. Both cancers have poor prognoses, with a 5-year survival rate <5% for metastatic disease [3][12]. Treatment combines surgery for early-stage disease and systemic therapy (e.g., gemcitabine/platinum regimens) for advanced cases, with emerging roles for targeted therapies and immunotherapy [2][14].
Population
Demographics: Females affected 2–6× more than males globally, with higher incidence among Native American, Hispanic, and Asian populations [1][5][17].
Geographic hotspots: Bolivia, Chile, South Korea, and Northern India report the highest rates [5][13].
Risk factors: Gallstones (>3 cm), chronic inflammation (e.g., primary sclerosing cholangitis), obesity, and Salmonella/H. pylori infections [8][12][17].
Burden
Mortality: 5-year survival <15% overall; drops to 2% for metastatic disease [3][12]. YLLs (years of life lost) account for 98.7% of disability-adjusted life years (DALYs) globally [7].
Trends: Age-standardized incidence declined globally (-14% since 1990), but absolute cases rose 1.85× due to population aging [3][7].
Disparities: Non-Hispanic Black Americans face rising incidence (+2.7% annual increase in late-stage tumors) despite overall declines in other groups [9].
Therapies
Localized disease: Radical resection (cholecystectomy ± liver/bile duct resection) for early-stage tumors [4][12]. Adjuvant chemotherapy (gemcitabine/cisplatin) or chemo-radiation improves relapse-free survival [6][10].
Advanced/metastatic disease: First-line gemcitabine/platinum combinations; immunotherapy (durvalumab + chemotherapy) shows promise (TOPAZ-1 trial) [2][14]. Palliative stenting for biliary obstruction [4][12].
Categories: rare hepatic diseases, rare neoplastic diseases, rare transplant-related disorders
Research Papers
1,064 drug discovery papers about Carcinoma of gallbladder and extrahepatic biliary tract, with 1 first-in-class and 11 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,064 drug discovery papers about Carcinoma of gallbladder and extrahepatic biliary tract, with 1 first-in-class and 11 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-06-15 | The interplay between bile acid metabolism and gut microbiome in biliary tract cancers.
The gut microbiota and bile acids (BAs) exist in a tightly regulated, bidirectional relationship that influences host metabolism, immune function, and disease. Primary BAs synthesized in the liver are chemically transformed by intestinal microbes into a diverse pool of secondary BAs, which exert antimicrobial effects and activate host signaling pathways including Farnesoid X Receptor (FXR), Takeda G protein-coupled receptor 5 (TGR5), and sphingosine-1-phosphate receptor 2 (S1PR2). These pathways regulate BA homeostasis, epithelial barrier integrity, inflammation, and carcinogenesis. Disruption of this BA-microbiome axis has been implicated in biliary tract cancers (BTCs), a group of aggressive malignancies with rising global incidence and limited therapeutic options. Secondary BAs and BA receptor signaling contribute to tumor initiation and progression through NF-κB activation, oxidative stress, and altered cell survival, whereas reduced FXR signaling and obstructed enterohepatic circulation further promote inflammatory dysregulation. Emerging evidence demonstrates that microbial dysbiosis and altered BA metabolism are associated with distinct BTC microbial profiles, enriched in taxa such as Fusobacterium, Salmonella, Prevotella, and Actinomyces, alongside depletion of commensals including Lactobacillus. These taxa influence inflammatory signaling, BA transformation, and epithelial injury, contributing to carcinogenesis. Microbiome-BA interactions also shape anti-tumor immunity and responses to immune checkpoint inhibitors (ICIs). Specific microbial signatures-particularly enrichment of Lachnospiraceae, Erysipelotrichaceae, Bacteroidetes, and Alistipes-correlate with enhanced immune activation and improved clinical outcomes in hepatobiliary cancers. Modulation of gut microbiota through antibiotics, probiotics, or fecal microbiota transplantation can influence BA composition, immune surveillance, and therapeutic efficacy. Collectively, these data highlight the central role of the BA-microbiome axis in BTC pathogenesis and treatment response. Microbial and BA metabolite profiling represent promising avenues for biomarker development, while targeted manipulation of BA signaling and microbial ecology offers potential therapeutic strategies to improve BTC outcomes.
2026-05-05 | Deciphering potential significances of biliary microbiome in cholelithiasis and cholangiocarcinoma.
This study aims to investigate the role of biliary microbiota (defined as the microbial community colonizing the biliary tract, including the gallbladder, intrahepatic and extrahepatic bile ducts) in the pathogenesis of cholelithiasis (CHOL) and cholangiocarcinoma (CCA), with a focus on the associations between microbial communities and these biliary diseases. We conducted a comprehensive bioinformatics analysis using high-throughput sequencing data obtained from the Sequence Read Archive (SRA) database to characterize the composition of microbial communities in patients with CCA and CHOL. We performed operational taxonomic unit (OTU) clustering, statistical analyses and Mendelian randomization (MR) to elucidate the causal relationships between specific bacterial strains and disease outcomes. Our findings revealed differences in the relative abundance of specific microbial taxa among research groups. The CCA + CHOL group exhibited a significant increase in the abundance of Fusobacteria, particularly Fusobacterium, compared to the Control or CCA group. This suggests a potential pathogenic role for these microorganisms in CHOL formation. Additionally, the CCA group demonstrated a higher diversity index, indicating that increased microbial diversity may contribute to the progression of the disease. MR analysis identified nominally significant statistical associations between specific bacterial strains. However, the presence of pleiotropy in some analyses necessitates caution when interpreting causal relationships. Our study highlights the complex interplay between biliary microbiota and the pathogenesis of CHOL and CCA. Modulating biliary microbiota may represent a promising therapeutic strategy for managing these diseases. Future research should focus on the functional roles of specific taxa in bile metabolism and immune modulation, ultimately improving our understanding of biliary health and disease management.
2026-01-10 | Consensus molecular subtypes and divergent genomic landscapes with clinical implications in biliary tract cancers.
600 Background: Biliary tract cancers (BTC), including cholangiocarcinomas and gallbladder adenocarcinomas, remain poorly understood. Stratifying this heterogeneous group of diseases based on molecular features may lead to novel precision treatments and yield urgently needed improvements in outcomes. Methods: We performed whole-genome and transcriptome sequencing of 165 laser-capture microdissected BTC tumors with paired normal tissues, representing 165 patients. First, we assigned all samples to 28 gene expression-based BTC signatures from nine previously published classifiers to create a signature similarity network. Using Markov clustering on the optimized network, we identified broad consensus molecular subtypes. Next, we used non-negative matrix factorization to decompose the consensus molecular subtype signatures into underlying components to identify associated cell types and processes. Finally, we integrated subtypes with de novo derived mutational signatures and drivers as well as electronic health records to search for prognostic and outcome implications. Results: Published subtyping classifications reflected only two underlying consensus molecular subtypes, which we named BTC-CMS-A and BTC-CMS-B. BTC-CMS-A tumors represented two thirds of intrahepatic cholangiocarcinomas and all mixed hepatocellular carcinomas, but no extrahepatic BTCs or gallbladder cancers, while BTC-CMS-B tumors were found along the whole biliary tract. BTC-CMS-B components exhibited markers of common bile duct epithelium but also shared expression profiles with intestinal Goblet cells, suggestive of an intestinal metaplasia histopathology. In contrast, BTC-CMS-A expressed hepatoblast markers while also exhibiting upregulation of pathways associated with kidney cell lineage. These results were validated by projecting all CMS-associated expression components onto two public single-cell RNAseq datasets. Of 16 drivers identified de novo from WGS, BAP1 and TP53 mutations were most frequent, mutually exclusive, and each was restricted to BTC-CMS-A and BTC-CMS-B, respectively. Mutational signature extraction revealed BTC-CMS-B tumors had increased tumor mutational burden and APOBEC-associated mutational signatures, whereas BTC-CMS-A was associated with increased non-homologous end-joining. Clinically, hepatitis B was more frequent in BTC-CMS-A cases, while patients with primary sclerosing cholangitis exclusively had BTC-CMS-B tumors. BTC-CMS-A was associated with significantly longer overall survival compared to CMS-B, after adjusting for clinically relevant covariates. This finding was validated in three external cohorts. Conclusions: BTC-CMS unify previous BTC classifications and display distinct clinical and genomic profiles and therefore should guide the development of targeted therapies and biomarker-driven trials.
2025-09-04 | Data from Generation of a Biliary Tract Cancer Cell Line Atlas Identifies Molecular Subtypes and Therapeutic Targets
<div>Abstract<p>Biliary tract cancers (BTC) are aggressive malignancies encompassing intrahepatic and extrahepatic cholangiocarcinoma, gallbladder carcinoma, and ampullary carcinoma. Here, we report integrative analysis of 63 BTC cell lines via multi-omics and genome-scale CRISPR screens. We identify widespread <i>EGFR</i> dependency in BTC, alongside dependencies selective to anatomic subtypes. Additionally, we delineate strategies to overcome therapeutic resistance, with combined EGFR inhibition potentiating targeting of <i>KRAS</i>-mutant and <i>FGFR2</i> fusion–driven models and SHP2 inhibition effective in the latter context. Clustering RNA/protein expression and dependencies data revealed functional relationships transcending single-gene alterations, with biliary, squamous, or dual biliary/hepatocyte lineage signatures stratifying BTC models. These subtypes exhibit distinct dependency profiles—including cell fate transcription factors <i>GRHL2</i>, <i>TP63</i>, and <i>HNF1B</i>, respectively—and demonstrate prognostic significance in patient samples. Potential subtype-specific targetable vulnerabilities include integrinα3 and the detoxification enzyme <i>UXS1</i>. This cell line atlas reveals therapeutic targets in molecularly defined BTCs, unveils disease subtypes, and provides a resource for therapeutic development.</p>Significance:<p>This integrative analysis of BTC cell lines defines the landscape of vulnerabilities across BTCs, stratifying distinct subtypes, and provides a key resource for studying disease heterogeneity. The findings highlight strategies for targeting BTCs with specific genomic alterations, as well as broader approaches based on shared molecular programs and essential pathways.</p></div>
2025-06-09 | Intrahepatic cholangiocarcinoma: Insights on molecular testing, targeted therapies, and future directions from a multidisciplinary panel.
Biliary tract cancers (BTCs) are a histologically and molecularly diverse group of malignancies arising from the gallbladder and the ductal epithelium of the biliary tree. Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver malignancy in the United States. Surgical resection with negative margins is the only recognized curative treatment option for iCCA; however, most patients will present with advanced or unresectable disease. The clinical presentation is largely non-specific, with the characteristic symptoms of biliary malignancies being less frequent than extrahepatic cholangiocarcinoma. Clinical management in iCCA is heavily influenced by the molecular profile of individual tumors. Hence, pathologists must exercise caution to prevent tissue exhaustion during the diagnostic workup of iCCA and ensure the availability of tissue samples for molecular testing. Establishing standardized procedures for obtaining adequate tissue and using molecular testing is vital. Circulating tumor DNA (ctDNA) offers a potential alternative to tissue-based analysis, especially in cases with insufficient tissue samples. Drugs targeting alterations in NTRK, IDH1, BRAF, FGFR2, and HER2 are commonly utilized. Targeting the MDM2-p53 pathway represents an avenue for future investigations in advanced BTCs. Liver transplantation and locoregional therapies are treatment modalities that may represent curative intent treatments for patients with unresectable disease, and larger explorations are warranted. Akin to HCC, a multidisciplinary team-based approach is essential for patients with BTCs. Through this narrative review of literature, we provide an overview of the current management of iCCA with perspectives regarding future directions in the clinical management of iCCA. We also present patient perspectives regarding the importance of patient advocacy and access to advances in clinical research for patients with BTCs.
antibodies
2026-05-28 | Zolbetuximab in CLDN18.2-positive biliary tract cancer after prior systemic therapy: A prospective observational pilot cohort study of early outcomes, safety, and patient-reported quality of life.
e16174 Background: CLDN18.2 is a validated therapeutic target in advanced gastric and gastroesophageal junction cancer; however, its role in biliary tract cancer (BTC; intrahepatic or extrahepatic cholangiocarcinoma, or gallbladder carcinoma) remains poorly defined. Immunohistochemical studies suggest that a subset of BTCs express CLDN18.2, but prospective clinical and quality-of-life (QoL) - focused data in BTC are lacking. Patients with advanced, pretreated BTC have limited treatment options after gemcitabine-based therapy. We conducted a prospective observational pilot cohort study to assess feasibility of prospective data capture, early clinical outcomes, safety, and patient-reported QoL among CLDN18.2-positive BTC patients receiving zolbetuximab in the salvage setting. Methods: This single-center, prospective, observational study included adults with unresectable or metastatic BTC treated between January 1, 2025, and December 15, 2025. Eligibility required CLDN18.2 expression in ≥50% of tumor cells (moderate/strong membranous staining) after progression on ≥1 prior systemic therapy. Patients received zolbetuximab in the salvage setting; monotherapy or combination with chemotherapy and dosing schedule (commonly every 3 weeks) were determined by the treating physician. Treatment decisions were at physician discretion; the study did not assign treatment or mandate dosing. The primary endpoint was change in EORTC QLQ-C30 global health status/QoL from baseline to week 6. Secondary endpoints included objective response rate (ORR), disease control rate (DCR), treatment duration, and treatment-emergent adverse events (TEAEs). Results: Seven eligible patients (ECOG 0-2) were included (median age 63 years, range 52-73); all had received ≥2 prior systemic lines. High CLDN18.2 expression (≥75%) was observed in 5/7 patients. ORR was 14% (1 partial response) and DCR was 57%. Median treatment duration was 3.4 months. Mean global health status/QoL improved from 52 to 63 at week 6 (+11 points); 4/7 patients achieved a clinically meaningful ≥10-point improvement. Pain (-15 points) and appetite loss (-12 points) improved most. Any-grade TEAEs occurred in 6/7 patients; grade ≥2 TEAEs occurred in 2/7. No treatment-related deaths occurred. Conclusions: In this prospective, biomarker-selected observational pilot cohort of heavily pretreated BTC, zolbetuximab use was feasible, showed encouraging disease control, and was associated with clinically meaningful QoL improvement. These hypothesis-generating data support further investigation of CLDN18.2-directed strategies in BTC.
2026-04-14 | Second-line Treatment Strategies in Biliary Tract Cancers
Biliary tract cancers (BTCs) are a highly heterogenous group of tumours arising from the bile ducts (cholangiocarcinoma [CCA]) and gallbladder. Of note, tumours of the ampulla of Vater typically fall under this definition but tend to be excluded from second-line treatment studies. Cholangiocarcinomas are further classified into intrahepatic (iCCA, including hilar) and extrahepatic (eCCA). Together, they account for approximately 15% of primary liver cancers and 3% of all gastrointestinal malignancies. However, iCCA and eCCA are separate entities that differ in incidence, clinical presentation, natural evolution, and molecular profile. Specifically, iCCA is less commonly associated with biliary obstructive symptoms and thus tends to be diagnosed incidentally and at a more advanced stage than eCCA. The diagnostic challenges partly stem from the localization of these tumours, deep in the hepatic and biliary systems, where it is often difficult to obtain a tissue biopsy or an adequate aspiration cytology. iCCA can be misclassified as carcinoma of unknown primary (CUP) as histologically it can be impossible to distinguish from metastatic adenocarcinoma of an extrahepatic primary tumour, and the primary tumour can be small and not well identified on imaging. The unique features of these tumours may in part explain their poor prognosis. Overall, the 5-year survival rate of CCA is estimated to be less than 25% for all stages combined, reflecting a very modest treatment effect. Chemoimmunotherapy combinations are now globally accepted as the standard first-line treatment, but uncertainties remain regarding second and later lines of treatment. This review will summarize the available treatments beyond the first line with a focus on the emerging field of molecular precision medicine.
2026-01-10 | ERBB2/HER2 status in biliary tract cancer patients in the Spanish RETUD registry.
498 Background: ERBB2 gene amplification or HER2 receptor overexpression is a well-known oncogenic driver and represents a therapeutic target in biliary tract cancer (BTC). We aimed to describe the epidemiology of a cohort of BTC patients (pt) according to HER2 status, treatment patterns and efficacy outcomes. Methods: We evaluated a real-world pt cohort from the Spanish RETUD registry, diagnosed with BTC from January 1st, 2017, to May 30th, 2025. Pt populations were defined as resectable disease (RD) for pt with neoadjuvant/adjuvant systemic therapy (ST) and/or radical treatment (surgery and/or locoregional treatment); and advanced disease (AD) for RC pt who experienced tumor relapse and those initially treated with first line ST. ERBB2/HER2 status was assessed by next-generation sequencing (NGS), immunohistochemistry (IHC), and/or fluorescence/chromogenic in situ hybridization (FISH/CISH). HER2+ status was considered as amplification with FISH/CISH (if IHQ++) or NGS, or overexpression (IHQ+++). Data included demographic and clinical characteristics, molecular profile, therapeutic procedures, and efficacy outcomes (EO). Progression-free survival (PFS), overall survival (OS) and time to next therapy (TTNT) were estimated using the Kaplan-Meier method. Results: ERBB2/HER2 status was determined in 448 BTC pt from 31 centers. At diagnosis (dx), 148 pt (33.0%) presented RD and 300 pt AD (67.0%). 128 RD pt experienced tumor relapse. HER2+ was confirmed in 5.4% pt and varied by tumor location: 3.3% in extrahepatic distal and intrahepatic cholangiocarcinoma, 7.3% in extrahepatic hilar and 15.3% in gallbladder carcinoma. Median (m) age at diagnosis in HER2+ pt was 63.8 years; with 75% of women. Treatments were administered in HER2+ and HER2- groups as follows: Surgery in 37.5% vs. 33.0%; locoregional therapy in 4.2% vs 11.6%, neoadjuvant/adjuvant ST in 20.8% vs. 21.7% and ST in AD pt in 100% vs 98.8%. A total of 29 pt (6.5%) received immunotherapy. Metastatic disease occurred in 87.5% of HER2+ vs 77.8% of HER2- pt. Regarding treatments in AD HER2+ pt, most frequent schemes for first and second line were CISGEM (70.6%) and FOLFOX (41.2%) and a total of 29.2% received anti-HER2 therapy. With a m (min, max) follow-up time for the overall population of 16.5 (0.9, 81.2) months (mo), mOS in AD HER2+ pt not treated with anti-HER2 therapies was 13.1 mo (95% CI 9.3-17.0) compared to 15.0 mo (95% CI 13.5-17.3) in HER2- pt (p=0.012) and 32.7 mo (95% CI 20.7-NA) in HER2+ treated pt (p=0.003). EO in first line for HER2+ vs HER2- pt: mPFS 6.6 mo (95% CI 4.5-8.1) vs 6.6 mo (95% CI 5.9-7.7) (p=0.075); mTTNT 7.8 mo (95% CI 6.7-NA) vs 10.0 mo (95% CI 9.2-11.2) (p=0.047); ORR 36.8% vs 27.8% (p = 0.393). Conclusions: This analysis provides insights into the characterization of real-world HER2+ BTC pt showing a significant impact in mOS upon treatment with anti-HER2 therapies.
2025-10-25 | Unveiling causal links between serum amino acid levels and risk of hepatobiliary neoplasms by Mendelian randomization study.
The causal links between serum amino acids (AAs) and hepatobiliary neoplasms remain unclear. This study aimed to systematically investigate these associations using Mendelian randomization (MR). Summary-level data on 20 serum AAs were obtained from publicly available genome-wide association studies. Genome-wide association studies data on hepatobiliary neoplasms - including primary liver cancer (PLC), hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), gallbladder and extrahepatic bile duct carcinoma, secondary liver cancer, benign liver tumors, and benign tumors of the extrahepatic bile ducts - were derived from FinnGen and 2 UK Biobank-based studies. A meta-analysis was conducted to calculate pooled effect sizes. Inverse variance weighting was the primary method, supplemented by MR-Egger, weighted median, MR.RAPS, maximum likelihood, and MR-PRESSO methods for sensitive analyses. Higher serum methionine was associated with lower risks of PLC (OR = 0.84, 95% CI: 0.72-0.97, P = .021) and HCC (OR = 0.87, 95% CI: 0.80-0.94, P < .001), but not ICC. Alanine increased PLC risk (OR = 1.19, 95% CI: 1.00-1.42, P = .047), with no significant effect on HCC or ICC. No AAs were linked to gallbladder and extrahepatic bile duct carcinoma or secondary liver cancer. For benign tumors, aspartate (OR = 1.13, 95% CI: 1.01-1.26, P = .037), cysteine (OR = 0.72, 95% CI: 0.57-0.92, P = .008), and lysine (OR = 1.49, 95% CI: 1.15-1.93, P = .003) were significantly associated with benign liver tumors or benign tumors of the extrahepatic bile ducts. This study offers robust evidence of causal associations between specific serum AAs and hepatobiliary neoplasms, emphasizing their potential as biomarkers and modifiable targets for early intervention.
2025-04-12 | Claudin 18.2: a promising actionable target in biliary tract cancers.
Anti-claudin 18.2 (anti-CLDN18.2) therapy has been approved for patients with CLDN18-positive gastric and gastroesophageal junction adenocarcinomas. The current study aims at evaluating the expression of CLDN18 in a large cohort of pathologically characterized biliary tract cancers (BTCs). A series of 237 BTCs were collected and reviewed under the BITCOIN protocol. All samples were assessed for CLDN18 status using immunohistochemistry (clone 43-14A). Tumor positivity for CLDN18 was determined if ≥75% of tumor cells exhibited moderate-to-strong membranous staining. CLDN18 expression was found in 29.5% of BTCs (70/237), with the highest rates in gallbladder carcinoma (GBC; 62.5%; 20/32) and extrahepatic cholangiocarcinoma (eCCA; 53.4%; 31/58), compared with intrahepatic cholangiocarcinoma (iCCA; 12.9%; 19/147) (P < 0.0001). CLDN18 positivity was detected in 5.5% of cases (13/237), most common in GBC (15.6%; 5/32), followed by eCCAs (8.6%; 5/58) and iCCAs (2.0%; 3/147) (P = 0.0045). Most CLDN18-positive samples (10/13) exhibited a heterogenous staining pattern. In iCCAs, large duct subtypes had higher CLDN18 expression [33.3% (10/30) versus 7.7% (9/117), P = 0.0002] and positivity [6.7% (2/30) versus 0.9% (1/117), P = 0.106] than small duct iCCAs. No significant differences were observed across GBC and eCCA histotypes, and CLDN18 was not associated with IDH1 or FGFR2 status in iCCAs. This study demonstrates that CLDN18 expression is present in a subset of BTCs, with significantly higher positivity rates in GBCs and eCCAs compared with iCCAs. In iCCAs, CLDN18 expression was more frequent in the large duct subtype but was not associated with IDH1 or FGFR2 status. These findings suggest that CLDN18 could be a potential therapeutic target in BTCs, warranting further prospective studies to evaluate its clinical significance and impact on patient outcomes.
oligonucleotides
2024-02-16 | M6A RNA methylation in biliary tract cancer: the function roles and potential therapeutic implications
Abstract Biliary tract cancers (BTCs) are relatively rare malignancies with a poor prognosis. For advanced BTCs, the efficacy of current chemotherapeutic approaches is limited. Consequently, there is an urgent need to deepen our understanding of the molecular mechanisms underlying BTC tumorigenesis and development for the exploration of effective targeted therapies. N6-methyladenosine (m6A), the most abundant RNA modifications in eukaryotes, is found usually dysregulated and involved in tumorigenesis, progression, and drug resistance in tumors. Numerous studies have confirmed that aberrant m6A regulators function as either oncogenes or tumor suppressors in BTCs by the reversible regulation of RNA metabolism, including splicing, export, degradation and translation. In this review, we summarized the current roles of the m6A regulators and their functional impacts on RNA fate in BTCs. The improved understanding of m6A modification in BTCs also provides a reasonable outlook for the exploration of new diagnostic strategies and efficient therapeutic targets.
2019-11-01 | <p>Receptor-Interacting Protein Kinase 1 Promotes Cholangiocarcinoma Proliferation And Lymphangiogenesis Through The Activation Protein 1 Pathway</p>
Receptor-interacting protein kinase 1 (RIPK1) is an important upstream regulator of multiple cell signaling pathways including inflammatory signals. RIPK1 is reported to be closely associated with the prognostic implications of cancer, especially epithelial tumors. But its role in proliferation and lymphangiogenesis in cholangiocarcinoma (CCA) remains unclear and requires further investigation.Expression of RIPK1 in human CCA tissues and CCA cell lines (QBC939, HUH28 and CCPL-1) was measured using qPCR, immunoblotting and immunohistochemistry. Silencing of RIPK1 was achieved by transduction of CCA cells via lentiviral plasmids (LV3-H1/GFP&Puro) encapsulating RIPK1 shRNA (LV-shRIPK1) or negative control shRNA (LV-shNC), and puromycin was used to select stable colonies. Proliferation and lymphangiogenesis were assessed in vitro by CCK-8 and matrigel-based tube formation assays, respectively. Activity of the activation protein-1 (AP-1) was evaluated by double-luciferase reporter gene assay. Protein expression of JNK, P38MAPK, ERK1/2, AP-1, P-AP-1, E-cadherin, N-cadherin and vascular endothelial growth factor-C (VEGF-C) was measured by immunoblotting or ELISA. An orthotopic CCA model in null mice was generated by transplanting QBC939 LV-shRIPK1, LV-shNC and control cells to further evaluate the role of RIPK1 on lymphangiogenesis in vivo. Immunohistochemistry was utilized to evaluate the expression of RIPK1 and VEGF-C, and tumor lymphatic vessels in the CCA model mice.Upregulated expression of RIPK1 in CCA tissues was closely related to tumor size, lymph node metastasis and poor prognosis. RIPK1 promoted proliferation and lymphangiogenesis in CCA cells, and regulated the activation of JNK and P38MAPK-mediated AP-1/VEGF-C pathway. Finally, in vivo animal experiments in the orthotopic CCA mouse model further confirmed the function of RIPK1 in lymphangiogenesis.This is the first report demonstrating the role of RIPK1 in proliferation and lymphangiogenesis through the MAPK (JNK and P38MAPK)- AP-1 pathway in CCA.
2018-06-28 | Enhanced expression of lncRNA TP73-AS1 predicts adverse phenotypes for cholangiocarcinoma and exerts oncogenic properties in vitro and in vivo
Cholangiocarcinoma (CCA) is one of the most aggressive malignancies with increasing incidence worldwide. Various evidence documents that abnormally expressed long non-coding RNAs (lncRNAs) play important roles in tumorigenesis and progression. TP73-AS1 is a novel cancer-related lncRNA that contributes to the development of several malignancies. However, its clinical value and potential effects on CCA remains unknown. RT-qPCR was used to measure the expression levels of TP73-AS1 in CCA tissues and paired non-tumor tissues and the association between TP73-AS1 expression and clinicopathological characteristics was analyzed. In addition, the functional roles of TP73-AS1 in CCA were detected both in vitro and in vivo. The results illustrated that TP73-AS1 transcription is enhanced in both CCA tissue samples and cell lines, and this upregulation is closely associated with larger tumor size (p=0.008) and advanced TNM stage (p=0.026) in patients with CCA. For the part of functional assays, silencing of TP73-AS1 could attenuate CCA cell growth both in vitro and in vivo. Additionally, silencing of TP73-AS1 facilitates apoptosis via activating caspase-3 and caspase-9. Importantly, TP73-AS1 expression did not affect HIBEC cell growth and apoptosis. Moreover, TP73-AS1 could also facilitate migration and invasion potential of CCA cells. Collectively, these findings may help to develop a potential therapeutic target for the patients with CCA.
2016-12-13 | Genetic alteration regulated by microRNAs in biliary tract cancers.
Biliary tract cancers (BTCs) constitute a relatively rare but highly malignant class of tumors with poor prognosis including gallbladder cancer, intra- and extra-hepatic cholangiocarcinoma. Recently, accumulated evidences have demonstrated that deregulated expression of microRNAs (miRNAs) is closely associated with the development, invasion, metastasis and prognosis of different cancers including BTCs. MiRNAs comprise an endogenously expressed and highly evolutionarily conserved group of small, non-coding, single-stranded RNAs which negatively regulate target genes expression by means of combining with 3' untranslated region (UTR) of corresponding mRNAs at the post-transcriptional level with significant roles in various fundamental cellular procedures including cell proliferation, differentiation, migration, cell cycle control and apoptosis. Recent studies have indicated that miRNAs could function as novel tumor-promoting genes or tumor suppressor genes to act as potential therapeutic targets in anticancer treatment because the genetic alteration regulated by miRNAs could result in tumorigenesis and tumor inhibition. Anomalous miRNAs expression patterns, acting as phenotypic signatures of distinct cancers, are promising to be used as diagnostic, prognostic, predictive biomarkers. In this review, we summarize the current findings from the studies about potential genetic alteration regulated by miRNAs and their roles in BTCs.
2016-05-04 | Septin 2 accelerates the progression of biliary tract cancer and is negatively regulated by mir-140-5p
Aberrant expression of septin family members (SEPTs) has been noticed in various carcinomas; however, few studies have been conducted to determine their function in biliary tract cancer (BTC). In this study, we identified SEPT2 as a tumor-promoting gene that is regulated by miR-140-5p in BTC. Although miR-140-5p has been reported to be an anti-oncomiR for several types of cancer, this has not previously been shown for BTC. We found that the expression levels of SEPT2 and miR-140-5p were inversely correlated; SEPT2 was aberrantly upregulated in both primary tumor specimens and cell lines whereas miR-140-5p was significantly downregulated. Ectopic expression of miR-140-5p markedly decreased SEPT2 protein concentration in BTC cells and suppressed cell proliferation and colony formation in vitro. Interaction between miR-140-5p and the 3'UTR of SEPT2 was confirmed by luciferase assays and rescue experiments. Furthermore, overexpression of SEPT2 and low expression of miR-140-5p were associated with increased invasion of BTC as indicated by clinical parameters and confirmed by invasion assays in vitro. Xenografts formation assay also showed that SEPT2 overexpression significantly facilitated the growth of tumor in vivo. This finding may provide a novel therapeutic strategy for the treatment of biliary tract cancer.
proteins
2026-01-10 | Epidemiological characterization of biliary tract cancer patients from the Spanish RETUD Registry.
503 Background: Biliary tract cancer (BTC) is a heterogeneous group of tumors, including cholangiocarcinoma (intra and extrahepatic) and gallbladder carcinoma (GC). We describe the epidemiology of BTC patients (pt) from the RETUD registry. Methods: We evaluated a large real-world cohort of pt diagnosed with BTC between January 1, 2017, and May 30, 2025. Analyses were based on first therapeutic approach as follows: resectable disease (RD) for patients with neoadjuvant/adjuvant therapy and/or radical treatment (surgery and/or locoregional therapy); and advanced disease (AD) for former patients who relapsed and those initially treated with first line therapy with/without other locoregional treatments. Analysis comprised demographic and clinical characteristics, tumor molecular profile, therapeutic procedures and efficacy outcomes (EO). Time to relapse (TTR) for RD, progression-free survival (PFS) for AD and overall survival (OS) for both were estimated using the Kaplan-Meier method. Results: A total of 1756 pt from 40 centers were classified as RD (695) or AD (1450). 389 (55,9%) pt were initially RD but progressed to AD. Median (m) age at diagnosis (dx) was 67.4 years (y), with 44.3% of women. Most frequent tumor locations at dx were intrahepatic (53.0%) and GC (15.5%). Distant metastasis in AD pt occurred primarily in liver (65.1%). 89.3% received chemotherapy, 10.7% were treated with immunotherapies, 6.3% received targeted therapies, and 7.7% of pt took part in at least one clinical trial. Biomarkers were determined in 553 pt (31.5%). ESCAT-I alterations were found in 176 pt (31.8%), most frequent ones are shown in table 1. RD pt: surgery was performed in 95.7%, locoregional therapy in 15.1% and 68.9% and 5.0% received adjuvant and neoadjuvant therapy respectively. With a m (p25, p75) follow-up of 23.9 months (mo) (14.4, 39.5), mOS was 33.0 mo (95% CI 30.2-38.9). mTTR was 19.4 mo (95% CI 17.3-22.2). AD pt: 1st and 2nd lines were administered to 96.4% and 42.6% pt. Most common schemes were CISGEM and FOLFOX, respectively. Thromboembolic events occurred in 17.3% of AD pt. With a m (p25, p75) follow-up of 13.2 mo (6.7, 22.9), mOS was 10.4 mo (95% CI 9.7-11.2). 1st line mPFS was 5.3 mo (95% CI 4.9-5.6). All pt: There were differences in mOS by age groups; 20.9 mo (95% CI 16.8-26.9) in <50 y pt vs 16.3 mo (95% CI 15.1-17.3) in ≥50 y pt (p=0.033); but not for sex; 16.3 mo (95% CI 14.9-17.9) in males vs 16.6 mo (95% CI 15.1-17.9) in females (p=0.444). Conclusions: This large multicenter real-world study provides a comprehensive characterization of BTC epidemiology in Spain. Treatment patterns observed, specifically those with IT and TT, reflect a progressive uptake of these innovative treatments in standard of care therapies. Most frequent ESCAT-I alterations. ESCAT-I Biomarker determination, N Alteration, N (%) IDH1 mutation 445 73 (16.4%) FGFR2 fusion 399 26 (6.5%) MSI 491 30 (6.1%) HER2 amplification/overexpression 448 24 (5.4%)
2024-04-12 | Unresectable biliary tract cancer: current and future systemic therapy
For decades, treatment of advanced biliary tract cancer (BTC) was confined to the use of chemotherapy. In recent years however, the number of therapeutic options available for patients with unresectable BTC have drastically increased, with immunotherapy and targeted treatment gradually joining the ranks of guideline-recommended treatment regimens. The aim of the present review is to summarise the current knowledge on unresectable BTC focusing on epidemiology, anatomical distribution and current strategies for systemic treatment. We further outline ongoing clinical trials and provide an outlook on future therapeutic interventions. In the realm of gastrointestinal malignancies, the increasing number of systemic treatment options for BTC is finally delivering on the longstanding commitment to personalised oncology. This emphasises the need for considering a comprehensive genomic-based pathology assessment right from the initial diagnosis to fully leverage the expanding array of therapeutic options that have recently become accessible.
2021-02-06 | The immunological characteristics of gallbladder carcinoma and advances in immunotherapy practices
Gallbladder carcinoma (GBC) is one of the most common malignant tumors in the biliary system, ranking sixth among gastrointestinal malignancies. In addition, the incidence of GBC has recently increased in China. GBC metastasizes early and invades adjacent organs such as the liver, making patients with GBC ineligible for radical surgery and giving them a poor prognosis. What is more, GBC is more inclined to develop chemo-resistance, which requires new strategies for clinical intervention. Cancer immunotherapy has made great advances over the past few years, with improved clinical efficacy against multiple malignancies, including GBC. This review summarizes the immunological characteristics of GBC as well as current advances in immunotherapies for GBC in order to provide new insights into future treatment and prevention of GBC.
2018-09-15 | Long-term survival of a patient with recurrent gallbladder carcinoma, treated with chemotherapy, immunotherapy, and surgery: a case report
Gallbladder cancer (GBC) is one of the refractory diseases. Multidisciplinary approach including immunotherapy for such cancers has received much attention in recent years. A 59-year-old man underwent an extended cholecystectomy for GBC (pathological stage II, T2 N0 M0, [per UICC 7th edition]) that was incidentally found during cholelithiasis surgery, and was then treated with adjuvant gemcitabine (GEM). Three months later, when a recurrence-suspected lesion was detected in segment 5 (S5) of his liver, we started adoptive immunotherapies with cytokine-activated killer (CAK) cell infusions, combined with chemotherapy. After a year of adjuvant immunochemotherapy, the S5 lesion disappeared on imaging, but lesions suspected metastatic recurrence again appeared in S7 and S8 at 4 years and 6 months post-surgery, for which GEM and cisplatin (CDDP) were administered as second-line chemotherapy. Immunochemotherapy produced stable disease (per RECIST) for 9 months, when tumor growth was detected; open microwave coagulo-necrotic therapy (MCN) was performed for these lesions. Three years after MCN, a solitary liver metastasis was detected in S4. MCN was conducted again, and peritoneal dissemination was found intraoperatively. A month after the second MCN, the patient’s carcinoembryonic antigen (CEA) level had increased. Therefore, GEM and tegafur-gimeracil-oteracil potassium (TS-1) were administered as third-line chemotherapy. We also switched the adoptive immunotherapy for tumor-associated antigen-pulsed dendritic cell-activated killer (DAK) cell immunotherapy. After nine courses of GEM and TS-1 administration, CEA had decreased to a normal level. At the time of reporting, 9 years and 6 months have passed since the initial surgery, and 18 months have passed since the peritoneal metastasis was detected. GEM and CDDP are currently administered as fourth-line chemotherapy because of re-increased CEA. Although an undeniable metastasis was found in his para-aortic lymph node, this patient visits our clinic regularly for immunotherapy. We here report a rare case of long-term survival of recurrent GBC well controlled by multidisciplinary therapy. Immunotherapy may be a promising modality among multidisciplinary methods for advanced cancer.
2017-11-01 | Immunotherapy as a treatment for biliary tract cancers: A review of approaches with an eye to the future
Biliary tract cancers (BTC) are aggressive malignancies associated with resistance to chemotherapy and poor prognostic rates. Therefore, novel treatment approaches are in need. Immunotherapy represents a promising breakthrough that uses a patient's immune system to target a tumor. This treatment approach has shown immense progress with positive results for selected cancers such as melanoma and nonsmall cell lung cancer. Initial preclinical data and preliminary clinical studies suggest encouraging mechanistic effects for immunotherapy in BTC offering the hope for an expanding therapeutic role for this disease. These approaches include targeted tumor antigen therapy via peptide and dendritic cell-based vaccines, allogenic cell adoptive immunotherapy, and the use of inhibitory agents targeting the immune checkpoint receptor pathway and multiple components of the tumor microenvironment. At this time demonstrating efficacy in larger clinical trials remains imperative. A multitude of ongoing trials aim to successfully translate mechanistic effects into antitumor efficacy and ultimately aim to incorporate immunotherapy into the routine management of BTC. With further research efforts, the optimization of dosing and therapeutic regimens, the identification of novel tumor antigens and a better understanding of alternative checkpoint pathway receptor expression may provide additional targets for rational combinatorial therapies which enhance the effects of immunotherapy and may offer hope for further advancing treatment options. Ultimately, the challenge remains to prospectively identify the subsets of patients with BTC who may respond to immunotherapy, and devising alternative strategies to sensitize those that do not with the hopes of improving outcomes for all with this deadly disease.
other
2023-01-08 | Immune-Markers in GallBladder Lesions and their Clinico-Diagnostic and Prognostic Significance - An Overview
Gallbladder benign diseases are common and usually cured without further consequences.Some benign illnesses increase the chance of cancer development significantly, whereas others resemble malignant disorders.The biomarkers discussed thus far are among the most extensively researched concerning the different diseases of GBC.Patients with gallbladder cancer are usually diagnosed in later stages when conventional treatments are ineffective.The lack of responsiveness of advanced instances of GBC to existing therapies necessitates the identification of novel prognostic and therapeutic approaches.Novel prognostic biomarkers may provide a crucial breakthrough in this area.Despite the available data and years of research, a prognostic marker that is 100% specific and sensitive to GBC is not yet available.A diverse number of molecular markers have been studied for their potential to be prognostic markers in GBC.p53 and HER2 have been studied very extensively and have shown promise.The deregulation and accumulation of the molecular markers we have discussed so far impact carcinogenesis of the gall bladder.Further analytical studies on the concentration levels of these markers in normal vs precancerous vs cancerous tissues should be carried out.Highly specific prognostic markers can help individualize treatment options to bring down the mortality rate in GBC.
2020-10-17 | Oncogenic KRAS–expressing organoids with biliary epithelial stem cell properties give rise to biliary tract cancer in mice
Abstract Biliary tract cancer (BTC) arises from biliary epithelial cells (BECs) and includes intrahepatic cholangiocarcinoma (IHCC), gallbladder cancer (GC), and extrahepatic cholangiocarcinoma (EHCC). Although frequent KRAS mutations and epigenetic changes at the INK4A/ARF locus have been identified, the molecular pathogenesis of BTC is unclear and the development of corresponding anticancer agents remains inadequate. We isolated epithelial cell adhesion molecule (EpCAM)–positive BECs from the mouse intrahepatic bile duct, gallbladder, and extrahepatic bile duct, and established organoids derived from these cells. Introduction of activated KRAS and homozygous deletion of Ink4a/Arf in the cells of each organoid type conferred the ability to form lethal metastatic adenocarcinoma with differentiated components and a pronounced desmoplastic reaction on cell transplantation into syngeneic mice, indicating that the manipulated cells correspond to BTC–initiating cells. The syngeneic mouse models recapitulate the pathological features of human IHCC, GC, and EHCC, and they should therefore prove useful for the investigation of BTC carcinogenesis and the development of new therapeutic strategies. Tumor cells isolated from primary tumors formed organoids in three‐dimensional culture, and serial syngeneic transplantation of these cells revealed that their cancer stem cell properties were supported by organoid culture, but not by adherent culture. Adherent culture thus attenuated tumorigenic activity as well as the expression of both epithelial and stem cell markers, whereas the expression of epithelial‐mesenchymal transition (EMT)–related transcription factor genes and mesenchymal cell markers was induced. Our data show that organoid culture is important for maintenance of epithelial cell characteristics, stemness, and tumorigenic activity of BTC–initiating cells.
2019-07-02 | Establishment of an organoid bank of biliary tract and pancreatic cancers and its application for personalized therapy and future treatment
Abstract Biliary tract cancers and pancreatic cancers are aggressive malignancies that are difficult to diagnose early and have a poor prognosis. Patients with inoperable biliary tract and pancreatic cancers generally receive chemotherapy regimens including gemcitabine. However, the effects of these drugs are limited, and the 5‐year survival rates of patients are very low. The newly developed three‐dimensional culture system known as “organoid culture” allows long‐term expansion of stem cells into cyst‐like structures (organoids) with properties resembling those of the original tissues. We and other groups have successfully established long‐term in vitro cultures of organoids derived from biliary tract and pancreatic cancers. Organoids derived from biliary tract and pancreatic cancers closely recapitulate the properties of the original tumors including genetic alterations, gene expression profiles, and histopathological structures. These patient‐derived cancer organoids can be applied for drug sensitivity testing, drug screening, epigenetic therapy, and differentiation‐inducing therapy to identify therapeutic agents optimal for each patient. We intend to further establish organoids derived from various cancer cases and construct an organoid bank of biliary tract and pancreatic cancers. These powerful in vitro preclinical models of refractory cancers may bridge the gap between basic research and clinical trials and allow personalized therapy for patients.
2017-04-01 | Mesothelin-targeting chimeric antigen receptor-modified T cells by piggyBac transposon system suppress the growth of bile duct carcinoma.
Chimeric antigen receptor modified T cell–based immunotherapy is revolutionizing the field of cancer treatment. However, its potential in treating bile duct carcinoma has not been fully explored. Herein, we developed the second-generation mesothelin-targeting chimeric antigen receptor–modified T cells with the 4-1BB co-stimulatory module by the piggyBac transposon system. Mesothelin-targeting chimeric antigen receptor was expressed by 66.0% of mesothelin-targeting chimeric antigen receptor–modified T cells post electrophoretic transfection and stimulation with K562-meso cells; the expressions of activation markers were tested by flow cytometry assay and showed greater activation of mesothelin-targeting chimeric antigen receptor–modified T cells than control T cells (CD107α: 71.9% vs 48.6%; CD27: 92.1% vs 61.8%; CD137: 55.5% vs 8.4%; CD28: 98.0% vs 82.1%; CD134: 37.5% vs 10.4%). Furthermore, mesothelin-targeting chimeric antigen receptor–modified T cells exerted cytotoxicity toward mesothelin-expressing EH-CA1b and EH-CA1a cells in an effector-to-target ratio-dependent manner, while leaving mesothelin-negative GSC-SD and EH-GB1 cells and normal liver L02 cells almost unharmed. Mesothelin-targeting chimeric antigen receptor–modified T cells secreted cytokines at higher levels when co-cultured with mesothelin-positive EH-CA1a and EH-CA1b cells than with mesothelin-negative GSC-SD and EH-GB1 cells. Enhanced cytotoxicity and cytokine secretion of mesothelin-targeting chimeric antigen receptor–modified T cells compared to control T cells were also observed when co-cultured with 293-meso cells (interferon γ: 85.1% ± 1.47% vs 8.3% ± 2.50%, p = 0.000; tumor necrosis factor α: 90.9% ± 4.67% vs 18.5% ± 3.62%, p = 0.0004; interleukin 2: 60.8% ± 2.00% vs 15.6% ± 2.06%, p = 0.002; interleukin 6: 6.4% ± 2.95% vs 1.7% ± 0.63%, p = 0.055). In addition, mesothelin-targeting chimeric antigen receptor–modified T cells showed greater inhibitory and proliferative capability than control T cells within EH-CA1a cell xenografts. This study shows the potential of mesothelin-targeting chimeric antigen receptor–modified T cells in treating bile duct carcinoma.
2014-08-22 | Retrohepatic inferior vena cava reconstruction with saphenous vein patch in advanced stage cholangiocarcinoma
Hepatic resection is the only known curative treatment option in primary and metastatic liver tumors. Unlike other types of malignancies, the response rate to even the best chemotherapy protocols is quite low in liver malignancies. Survival is expressed in months in untreated liver malignancies or in patients with residual tumor after resection. The optimal survival can be achieved only by liver resection with negative surgical margins. In order to increase the number of patients suitable for hepatic resection, techniques such as portal vein embolization, neoadjuvant chemotherapy, two-step hepatectomy, re-do hepatectomy, hypothermic liver perfusion have been developed and newer modalities are still being investigated. Primary liver malignancies like hepatocellular carcinoma and cholangiocarcinoma, and metastatic liver tumors can invade the retrohepatic vena cava due to anatomical proximity. Invasion of either the hepatocaval confluence or vena cava are often considered as contraindications for liver resection due to the risk of intraoperative massive air embolism or hemorrhage. In this article, we present a patient who underwent left hepatectomy together with vena cava resection and reconstruction with saphenous vein patch due to cholangiocarcinoma.
small molecules
2026-06-15 | The interplay between bile acid metabolism and gut microbiome in biliary tract cancers.
The gut microbiota and bile acids (BAs) exist in a tightly regulated, bidirectional relationship that influences host metabolism, immune function, and disease. Primary BAs synthesized in the liver are chemically transformed by intestinal microbes into a diverse pool of secondary BAs, which exert antimicrobial effects and activate host signaling pathways including Farnesoid X Receptor (FXR), Takeda G protein-coupled receptor 5 (TGR5), and sphingosine-1-phosphate receptor 2 (S1PR2). These pathways regulate BA homeostasis, epithelial barrier integrity, inflammation, and carcinogenesis. Disruption of this BA-microbiome axis has been implicated in biliary tract cancers (BTCs), a group of aggressive malignancies with rising global incidence and limited therapeutic options. Secondary BAs and BA receptor signaling contribute to tumor initiation and progression through NF-κB activation, oxidative stress, and altered cell survival, whereas reduced FXR signaling and obstructed enterohepatic circulation further promote inflammatory dysregulation. Emerging evidence demonstrates that microbial dysbiosis and altered BA metabolism are associated with distinct BTC microbial profiles, enriched in taxa such as Fusobacterium, Salmonella, Prevotella, and Actinomyces, alongside depletion of commensals including Lactobacillus. These taxa influence inflammatory signaling, BA transformation, and epithelial injury, contributing to carcinogenesis. Microbiome-BA interactions also shape anti-tumor immunity and responses to immune checkpoint inhibitors (ICIs). Specific microbial signatures-particularly enrichment of Lachnospiraceae, Erysipelotrichaceae, Bacteroidetes, and Alistipes-correlate with enhanced immune activation and improved clinical outcomes in hepatobiliary cancers. Modulation of gut microbiota through antibiotics, probiotics, or fecal microbiota transplantation can influence BA composition, immune surveillance, and therapeutic efficacy. Collectively, these data highlight the central role of the BA-microbiome axis in BTC pathogenesis and treatment response. Microbial and BA metabolite profiling represent promising avenues for biomarker development, while targeted manipulation of BA signaling and microbial ecology offers potential therapeutic strategies to improve BTC outcomes.
2026-05-05 | Deciphering potential significances of biliary microbiome in cholelithiasis and cholangiocarcinoma.
This study aims to investigate the role of biliary microbiota (defined as the microbial community colonizing the biliary tract, including the gallbladder, intrahepatic and extrahepatic bile ducts) in the pathogenesis of cholelithiasis (CHOL) and cholangiocarcinoma (CCA), with a focus on the associations between microbial communities and these biliary diseases. We conducted a comprehensive bioinformatics analysis using high-throughput sequencing data obtained from the Sequence Read Archive (SRA) database to characterize the composition of microbial communities in patients with CCA and CHOL. We performed operational taxonomic unit (OTU) clustering, statistical analyses and Mendelian randomization (MR) to elucidate the causal relationships between specific bacterial strains and disease outcomes. Our findings revealed differences in the relative abundance of specific microbial taxa among research groups. The CCA + CHOL group exhibited a significant increase in the abundance of Fusobacteria, particularly Fusobacterium, compared to the Control or CCA group. This suggests a potential pathogenic role for these microorganisms in CHOL formation. Additionally, the CCA group demonstrated a higher diversity index, indicating that increased microbial diversity may contribute to the progression of the disease. MR analysis identified nominally significant statistical associations between specific bacterial strains. However, the presence of pleiotropy in some analyses necessitates caution when interpreting causal relationships. Our study highlights the complex interplay between biliary microbiota and the pathogenesis of CHOL and CCA. Modulating biliary microbiota may represent a promising therapeutic strategy for managing these diseases. Future research should focus on the functional roles of specific taxa in bile metabolism and immune modulation, ultimately improving our understanding of biliary health and disease management.
2026-01-10 | Consensus molecular subtypes and divergent genomic landscapes with clinical implications in biliary tract cancers.
600 Background: Biliary tract cancers (BTC), including cholangiocarcinomas and gallbladder adenocarcinomas, remain poorly understood. Stratifying this heterogeneous group of diseases based on molecular features may lead to novel precision treatments and yield urgently needed improvements in outcomes. Methods: We performed whole-genome and transcriptome sequencing of 165 laser-capture microdissected BTC tumors with paired normal tissues, representing 165 patients. First, we assigned all samples to 28 gene expression-based BTC signatures from nine previously published classifiers to create a signature similarity network. Using Markov clustering on the optimized network, we identified broad consensus molecular subtypes. Next, we used non-negative matrix factorization to decompose the consensus molecular subtype signatures into underlying components to identify associated cell types and processes. Finally, we integrated subtypes with de novo derived mutational signatures and drivers as well as electronic health records to search for prognostic and outcome implications. Results: Published subtyping classifications reflected only two underlying consensus molecular subtypes, which we named BTC-CMS-A and BTC-CMS-B. BTC-CMS-A tumors represented two thirds of intrahepatic cholangiocarcinomas and all mixed hepatocellular carcinomas, but no extrahepatic BTCs or gallbladder cancers, while BTC-CMS-B tumors were found along the whole biliary tract. BTC-CMS-B components exhibited markers of common bile duct epithelium but also shared expression profiles with intestinal Goblet cells, suggestive of an intestinal metaplasia histopathology. In contrast, BTC-CMS-A expressed hepatoblast markers while also exhibiting upregulation of pathways associated with kidney cell lineage. These results were validated by projecting all CMS-associated expression components onto two public single-cell RNAseq datasets. Of 16 drivers identified de novo from WGS, BAP1 and TP53 mutations were most frequent, mutually exclusive, and each was restricted to BTC-CMS-A and BTC-CMS-B, respectively. Mutational signature extraction revealed BTC-CMS-B tumors had increased tumor mutational burden and APOBEC-associated mutational signatures, whereas BTC-CMS-A was associated with increased non-homologous end-joining. Clinically, hepatitis B was more frequent in BTC-CMS-A cases, while patients with primary sclerosing cholangitis exclusively had BTC-CMS-B tumors. BTC-CMS-A was associated with significantly longer overall survival compared to CMS-B, after adjusting for clinically relevant covariates. This finding was validated in three external cohorts. Conclusions: BTC-CMS unify previous BTC classifications and display distinct clinical and genomic profiles and therefore should guide the development of targeted therapies and biomarker-driven trials.
2025-09-04 | Data from Generation of a Biliary Tract Cancer Cell Line Atlas Identifies Molecular Subtypes and Therapeutic Targets
<div>Abstract<p>Biliary tract cancers (BTC) are aggressive malignancies encompassing intrahepatic and extrahepatic cholangiocarcinoma, gallbladder carcinoma, and ampullary carcinoma. Here, we report integrative analysis of 63 BTC cell lines via multi-omics and genome-scale CRISPR screens. We identify widespread <i>EGFR</i> dependency in BTC, alongside dependencies selective to anatomic subtypes. Additionally, we delineate strategies to overcome therapeutic resistance, with combined EGFR inhibition potentiating targeting of <i>KRAS</i>-mutant and <i>FGFR2</i> fusion–driven models and SHP2 inhibition effective in the latter context. Clustering RNA/protein expression and dependencies data revealed functional relationships transcending single-gene alterations, with biliary, squamous, or dual biliary/hepatocyte lineage signatures stratifying BTC models. These subtypes exhibit distinct dependency profiles—including cell fate transcription factors <i>GRHL2</i>, <i>TP63</i>, and <i>HNF1B</i>, respectively—and demonstrate prognostic significance in patient samples. Potential subtype-specific targetable vulnerabilities include integrinα3 and the detoxification enzyme <i>UXS1</i>. This cell line atlas reveals therapeutic targets in molecularly defined BTCs, unveils disease subtypes, and provides a resource for therapeutic development.</p>Significance:<p>This integrative analysis of BTC cell lines defines the landscape of vulnerabilities across BTCs, stratifying distinct subtypes, and provides a key resource for studying disease heterogeneity. The findings highlight strategies for targeting BTCs with specific genomic alterations, as well as broader approaches based on shared molecular programs and essential pathways.</p></div>
2025-06-09 | Intrahepatic cholangiocarcinoma: Insights on molecular testing, targeted therapies, and future directions from a multidisciplinary panel.
Biliary tract cancers (BTCs) are a histologically and molecularly diverse group of malignancies arising from the gallbladder and the ductal epithelium of the biliary tree. Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver malignancy in the United States. Surgical resection with negative margins is the only recognized curative treatment option for iCCA; however, most patients will present with advanced or unresectable disease. The clinical presentation is largely non-specific, with the characteristic symptoms of biliary malignancies being less frequent than extrahepatic cholangiocarcinoma. Clinical management in iCCA is heavily influenced by the molecular profile of individual tumors. Hence, pathologists must exercise caution to prevent tissue exhaustion during the diagnostic workup of iCCA and ensure the availability of tissue samples for molecular testing. Establishing standardized procedures for obtaining adequate tissue and using molecular testing is vital. Circulating tumor DNA (ctDNA) offers a potential alternative to tissue-based analysis, especially in cases with insufficient tissue samples. Drugs targeting alterations in NTRK, IDH1, BRAF, FGFR2, and HER2 are commonly utilized. Targeting the MDM2-p53 pathway represents an avenue for future investigations in advanced BTCs. Liver transplantation and locoregional therapies are treatment modalities that may represent curative intent treatments for patients with unresectable disease, and larger explorations are warranted. Akin to HCC, a multidisciplinary team-based approach is essential for patients with BTCs. Through this narrative review of literature, we provide an overview of the current management of iCCA with perspectives regarding future directions in the clinical management of iCCA. We also present patient perspectives regarding the importance of patient advocacy and access to advances in clinical research for patients with BTCs.
antibodies
2026-05-28 | Zolbetuximab in CLDN18.2-positive biliary tract cancer after prior systemic therapy: A prospective observational pilot cohort study of early outcomes, safety, and patient-reported quality of life.
e16174 Background: CLDN18.2 is a validated therapeutic target in advanced gastric and gastroesophageal junction cancer; however, its role in biliary tract cancer (BTC; intrahepatic or extrahepatic cholangiocarcinoma, or gallbladder carcinoma) remains poorly defined. Immunohistochemical studies suggest that a subset of BTCs express CLDN18.2, but prospective clinical and quality-of-life (QoL) - focused data in BTC are lacking. Patients with advanced, pretreated BTC have limited treatment options after gemcitabine-based therapy. We conducted a prospective observational pilot cohort study to assess feasibility of prospective data capture, early clinical outcomes, safety, and patient-reported QoL among CLDN18.2-positive BTC patients receiving zolbetuximab in the salvage setting. Methods: This single-center, prospective, observational study included adults with unresectable or metastatic BTC treated between January 1, 2025, and December 15, 2025. Eligibility required CLDN18.2 expression in ≥50% of tumor cells (moderate/strong membranous staining) after progression on ≥1 prior systemic therapy. Patients received zolbetuximab in the salvage setting; monotherapy or combination with chemotherapy and dosing schedule (commonly every 3 weeks) were determined by the treating physician. Treatment decisions were at physician discretion; the study did not assign treatment or mandate dosing. The primary endpoint was change in EORTC QLQ-C30 global health status/QoL from baseline to week 6. Secondary endpoints included objective response rate (ORR), disease control rate (DCR), treatment duration, and treatment-emergent adverse events (TEAEs). Results: Seven eligible patients (ECOG 0-2) were included (median age 63 years, range 52-73); all had received ≥2 prior systemic lines. High CLDN18.2 expression (≥75%) was observed in 5/7 patients. ORR was 14% (1 partial response) and DCR was 57%. Median treatment duration was 3.4 months. Mean global health status/QoL improved from 52 to 63 at week 6 (+11 points); 4/7 patients achieved a clinically meaningful ≥10-point improvement. Pain (-15 points) and appetite loss (-12 points) improved most. Any-grade TEAEs occurred in 6/7 patients; grade ≥2 TEAEs occurred in 2/7. No treatment-related deaths occurred. Conclusions: In this prospective, biomarker-selected observational pilot cohort of heavily pretreated BTC, zolbetuximab use was feasible, showed encouraging disease control, and was associated with clinically meaningful QoL improvement. These hypothesis-generating data support further investigation of CLDN18.2-directed strategies in BTC.
2026-04-14 | Second-line Treatment Strategies in Biliary Tract Cancers
Biliary tract cancers (BTCs) are a highly heterogenous group of tumours arising from the bile ducts (cholangiocarcinoma [CCA]) and gallbladder. Of note, tumours of the ampulla of Vater typically fall under this definition but tend to be excluded from second-line treatment studies. Cholangiocarcinomas are further classified into intrahepatic (iCCA, including hilar) and extrahepatic (eCCA). Together, they account for approximately 15% of primary liver cancers and 3% of all gastrointestinal malignancies. However, iCCA and eCCA are separate entities that differ in incidence, clinical presentation, natural evolution, and molecular profile. Specifically, iCCA is less commonly associated with biliary obstructive symptoms and thus tends to be diagnosed incidentally and at a more advanced stage than eCCA. The diagnostic challenges partly stem from the localization of these tumours, deep in the hepatic and biliary systems, where it is often difficult to obtain a tissue biopsy or an adequate aspiration cytology. iCCA can be misclassified as carcinoma of unknown primary (CUP) as histologically it can be impossible to distinguish from metastatic adenocarcinoma of an extrahepatic primary tumour, and the primary tumour can be small and not well identified on imaging. The unique features of these tumours may in part explain their poor prognosis. Overall, the 5-year survival rate of CCA is estimated to be less than 25% for all stages combined, reflecting a very modest treatment effect. Chemoimmunotherapy combinations are now globally accepted as the standard first-line treatment, but uncertainties remain regarding second and later lines of treatment. This review will summarize the available treatments beyond the first line with a focus on the emerging field of molecular precision medicine.
2026-01-10 | ERBB2/HER2 status in biliary tract cancer patients in the Spanish RETUD registry.
498 Background: ERBB2 gene amplification or HER2 receptor overexpression is a well-known oncogenic driver and represents a therapeutic target in biliary tract cancer (BTC). We aimed to describe the epidemiology of a cohort of BTC patients (pt) according to HER2 status, treatment patterns and efficacy outcomes. Methods: We evaluated a real-world pt cohort from the Spanish RETUD registry, diagnosed with BTC from January 1st, 2017, to May 30th, 2025. Pt populations were defined as resectable disease (RD) for pt with neoadjuvant/adjuvant systemic therapy (ST) and/or radical treatment (surgery and/or locoregional treatment); and advanced disease (AD) for RC pt who experienced tumor relapse and those initially treated with first line ST. ERBB2/HER2 status was assessed by next-generation sequencing (NGS), immunohistochemistry (IHC), and/or fluorescence/chromogenic in situ hybridization (FISH/CISH). HER2+ status was considered as amplification with FISH/CISH (if IHQ++) or NGS, or overexpression (IHQ+++). Data included demographic and clinical characteristics, molecular profile, therapeutic procedures, and efficacy outcomes (EO). Progression-free survival (PFS), overall survival (OS) and time to next therapy (TTNT) were estimated using the Kaplan-Meier method. Results: ERBB2/HER2 status was determined in 448 BTC pt from 31 centers. At diagnosis (dx), 148 pt (33.0%) presented RD and 300 pt AD (67.0%). 128 RD pt experienced tumor relapse. HER2+ was confirmed in 5.4% pt and varied by tumor location: 3.3% in extrahepatic distal and intrahepatic cholangiocarcinoma, 7.3% in extrahepatic hilar and 15.3% in gallbladder carcinoma. Median (m) age at diagnosis in HER2+ pt was 63.8 years; with 75% of women. Treatments were administered in HER2+ and HER2- groups as follows: Surgery in 37.5% vs. 33.0%; locoregional therapy in 4.2% vs 11.6%, neoadjuvant/adjuvant ST in 20.8% vs. 21.7% and ST in AD pt in 100% vs 98.8%. A total of 29 pt (6.5%) received immunotherapy. Metastatic disease occurred in 87.5% of HER2+ vs 77.8% of HER2- pt. Regarding treatments in AD HER2+ pt, most frequent schemes for first and second line were CISGEM (70.6%) and FOLFOX (41.2%) and a total of 29.2% received anti-HER2 therapy. With a m (min, max) follow-up time for the overall population of 16.5 (0.9, 81.2) months (mo), mOS in AD HER2+ pt not treated with anti-HER2 therapies was 13.1 mo (95% CI 9.3-17.0) compared to 15.0 mo (95% CI 13.5-17.3) in HER2- pt (p=0.012) and 32.7 mo (95% CI 20.7-NA) in HER2+ treated pt (p=0.003). EO in first line for HER2+ vs HER2- pt: mPFS 6.6 mo (95% CI 4.5-8.1) vs 6.6 mo (95% CI 5.9-7.7) (p=0.075); mTTNT 7.8 mo (95% CI 6.7-NA) vs 10.0 mo (95% CI 9.2-11.2) (p=0.047); ORR 36.8% vs 27.8% (p = 0.393). Conclusions: This analysis provides insights into the characterization of real-world HER2+ BTC pt showing a significant impact in mOS upon treatment with anti-HER2 therapies.
2025-10-25 | Unveiling causal links between serum amino acid levels and risk of hepatobiliary neoplasms by Mendelian randomization study.
The causal links between serum amino acids (AAs) and hepatobiliary neoplasms remain unclear. This study aimed to systematically investigate these associations using Mendelian randomization (MR). Summary-level data on 20 serum AAs were obtained from publicly available genome-wide association studies. Genome-wide association studies data on hepatobiliary neoplasms - including primary liver cancer (PLC), hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), gallbladder and extrahepatic bile duct carcinoma, secondary liver cancer, benign liver tumors, and benign tumors of the extrahepatic bile ducts - were derived from FinnGen and 2 UK Biobank-based studies. A meta-analysis was conducted to calculate pooled effect sizes. Inverse variance weighting was the primary method, supplemented by MR-Egger, weighted median, MR.RAPS, maximum likelihood, and MR-PRESSO methods for sensitive analyses. Higher serum methionine was associated with lower risks of PLC (OR = 0.84, 95% CI: 0.72-0.97, P = .021) and HCC (OR = 0.87, 95% CI: 0.80-0.94, P < .001), but not ICC. Alanine increased PLC risk (OR = 1.19, 95% CI: 1.00-1.42, P = .047), with no significant effect on HCC or ICC. No AAs were linked to gallbladder and extrahepatic bile duct carcinoma or secondary liver cancer. For benign tumors, aspartate (OR = 1.13, 95% CI: 1.01-1.26, P = .037), cysteine (OR = 0.72, 95% CI: 0.57-0.92, P = .008), and lysine (OR = 1.49, 95% CI: 1.15-1.93, P = .003) were significantly associated with benign liver tumors or benign tumors of the extrahepatic bile ducts. This study offers robust evidence of causal associations between specific serum AAs and hepatobiliary neoplasms, emphasizing their potential as biomarkers and modifiable targets for early intervention.
2025-04-12 | Claudin 18.2: a promising actionable target in biliary tract cancers.
Anti-claudin 18.2 (anti-CLDN18.2) therapy has been approved for patients with CLDN18-positive gastric and gastroesophageal junction adenocarcinomas. The current study aims at evaluating the expression of CLDN18 in a large cohort of pathologically characterized biliary tract cancers (BTCs). A series of 237 BTCs were collected and reviewed under the BITCOIN protocol. All samples were assessed for CLDN18 status using immunohistochemistry (clone 43-14A). Tumor positivity for CLDN18 was determined if ≥75% of tumor cells exhibited moderate-to-strong membranous staining. CLDN18 expression was found in 29.5% of BTCs (70/237), with the highest rates in gallbladder carcinoma (GBC; 62.5%; 20/32) and extrahepatic cholangiocarcinoma (eCCA; 53.4%; 31/58), compared with intrahepatic cholangiocarcinoma (iCCA; 12.9%; 19/147) (P < 0.0001). CLDN18 positivity was detected in 5.5% of cases (13/237), most common in GBC (15.6%; 5/32), followed by eCCAs (8.6%; 5/58) and iCCAs (2.0%; 3/147) (P = 0.0045). Most CLDN18-positive samples (10/13) exhibited a heterogenous staining pattern. In iCCAs, large duct subtypes had higher CLDN18 expression [33.3% (10/30) versus 7.7% (9/117), P = 0.0002] and positivity [6.7% (2/30) versus 0.9% (1/117), P = 0.106] than small duct iCCAs. No significant differences were observed across GBC and eCCA histotypes, and CLDN18 was not associated with IDH1 or FGFR2 status in iCCAs. This study demonstrates that CLDN18 expression is present in a subset of BTCs, with significantly higher positivity rates in GBCs and eCCAs compared with iCCAs. In iCCAs, CLDN18 expression was more frequent in the large duct subtype but was not associated with IDH1 or FGFR2 status. These findings suggest that CLDN18 could be a potential therapeutic target in BTCs, warranting further prospective studies to evaluate its clinical significance and impact on patient outcomes.
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2024-02-16 | M6A RNA methylation in biliary tract cancer: the function roles and potential therapeutic implications
Abstract Biliary tract cancers (BTCs) are relatively rare malignancies with a poor prognosis. For advanced BTCs, the efficacy of current chemotherapeutic approaches is limited. Consequently, there is an urgent need to deepen our understanding of the molecular mechanisms underlying BTC tumorigenesis and development for the exploration of effective targeted therapies. N6-methyladenosine (m6A), the most abundant RNA modifications in eukaryotes, is found usually dysregulated and involved in tumorigenesis, progression, and drug resistance in tumors. Numerous studies have confirmed that aberrant m6A regulators function as either oncogenes or tumor suppressors in BTCs by the reversible regulation of RNA metabolism, including splicing, export, degradation and translation. In this review, we summarized the current roles of the m6A regulators and their functional impacts on RNA fate in BTCs. The improved understanding of m6A modification in BTCs also provides a reasonable outlook for the exploration of new diagnostic strategies and efficient therapeutic targets.
2019-11-01 | <p>Receptor-Interacting Protein Kinase 1 Promotes Cholangiocarcinoma Proliferation And Lymphangiogenesis Through The Activation Protein 1 Pathway</p>
Receptor-interacting protein kinase 1 (RIPK1) is an important upstream regulator of multiple cell signaling pathways including inflammatory signals. RIPK1 is reported to be closely associated with the prognostic implications of cancer, especially epithelial tumors. But its role in proliferation and lymphangiogenesis in cholangiocarcinoma (CCA) remains unclear and requires further investigation.Expression of RIPK1 in human CCA tissues and CCA cell lines (QBC939, HUH28 and CCPL-1) was measured using qPCR, immunoblotting and immunohistochemistry. Silencing of RIPK1 was achieved by transduction of CCA cells via lentiviral plasmids (LV3-H1/GFP&Puro) encapsulating RIPK1 shRNA (LV-shRIPK1) or negative control shRNA (LV-shNC), and puromycin was used to select stable colonies. Proliferation and lymphangiogenesis were assessed in vitro by CCK-8 and matrigel-based tube formation assays, respectively. Activity of the activation protein-1 (AP-1) was evaluated by double-luciferase reporter gene assay. Protein expression of JNK, P38MAPK, ERK1/2, AP-1, P-AP-1, E-cadherin, N-cadherin and vascular endothelial growth factor-C (VEGF-C) was measured by immunoblotting or ELISA. An orthotopic CCA model in null mice was generated by transplanting QBC939 LV-shRIPK1, LV-shNC and control cells to further evaluate the role of RIPK1 on lymphangiogenesis in vivo. Immunohistochemistry was utilized to evaluate the expression of RIPK1 and VEGF-C, and tumor lymphatic vessels in the CCA model mice.Upregulated expression of RIPK1 in CCA tissues was closely related to tumor size, lymph node metastasis and poor prognosis. RIPK1 promoted proliferation and lymphangiogenesis in CCA cells, and regulated the activation of JNK and P38MAPK-mediated AP-1/VEGF-C pathway. Finally, in vivo animal experiments in the orthotopic CCA mouse model further confirmed the function of RIPK1 in lymphangiogenesis.This is the first report demonstrating the role of RIPK1 in proliferation and lymphangiogenesis through the MAPK (JNK and P38MAPK)- AP-1 pathway in CCA.
2018-06-28 | Enhanced expression of lncRNA TP73-AS1 predicts adverse phenotypes for cholangiocarcinoma and exerts oncogenic properties in vitro and in vivo
Cholangiocarcinoma (CCA) is one of the most aggressive malignancies with increasing incidence worldwide. Various evidence documents that abnormally expressed long non-coding RNAs (lncRNAs) play important roles in tumorigenesis and progression. TP73-AS1 is a novel cancer-related lncRNA that contributes to the development of several malignancies. However, its clinical value and potential effects on CCA remains unknown. RT-qPCR was used to measure the expression levels of TP73-AS1 in CCA tissues and paired non-tumor tissues and the association between TP73-AS1 expression and clinicopathological characteristics was analyzed. In addition, the functional roles of TP73-AS1 in CCA were detected both in vitro and in vivo. The results illustrated that TP73-AS1 transcription is enhanced in both CCA tissue samples and cell lines, and this upregulation is closely associated with larger tumor size (p=0.008) and advanced TNM stage (p=0.026) in patients with CCA. For the part of functional assays, silencing of TP73-AS1 could attenuate CCA cell growth both in vitro and in vivo. Additionally, silencing of TP73-AS1 facilitates apoptosis via activating caspase-3 and caspase-9. Importantly, TP73-AS1 expression did not affect HIBEC cell growth and apoptosis. Moreover, TP73-AS1 could also facilitate migration and invasion potential of CCA cells. Collectively, these findings may help to develop a potential therapeutic target for the patients with CCA.
2016-12-13 | Genetic alteration regulated by microRNAs in biliary tract cancers.
Biliary tract cancers (BTCs) constitute a relatively rare but highly malignant class of tumors with poor prognosis including gallbladder cancer, intra- and extra-hepatic cholangiocarcinoma. Recently, accumulated evidences have demonstrated that deregulated expression of microRNAs (miRNAs) is closely associated with the development, invasion, metastasis and prognosis of different cancers including BTCs. MiRNAs comprise an endogenously expressed and highly evolutionarily conserved group of small, non-coding, single-stranded RNAs which negatively regulate target genes expression by means of combining with 3' untranslated region (UTR) of corresponding mRNAs at the post-transcriptional level with significant roles in various fundamental cellular procedures including cell proliferation, differentiation, migration, cell cycle control and apoptosis. Recent studies have indicated that miRNAs could function as novel tumor-promoting genes or tumor suppressor genes to act as potential therapeutic targets in anticancer treatment because the genetic alteration regulated by miRNAs could result in tumorigenesis and tumor inhibition. Anomalous miRNAs expression patterns, acting as phenotypic signatures of distinct cancers, are promising to be used as diagnostic, prognostic, predictive biomarkers. In this review, we summarize the current findings from the studies about potential genetic alteration regulated by miRNAs and their roles in BTCs.
2016-05-04 | Septin 2 accelerates the progression of biliary tract cancer and is negatively regulated by mir-140-5p
Aberrant expression of septin family members (SEPTs) has been noticed in various carcinomas; however, few studies have been conducted to determine their function in biliary tract cancer (BTC). In this study, we identified SEPT2 as a tumor-promoting gene that is regulated by miR-140-5p in BTC. Although miR-140-5p has been reported to be an anti-oncomiR for several types of cancer, this has not previously been shown for BTC. We found that the expression levels of SEPT2 and miR-140-5p were inversely correlated; SEPT2 was aberrantly upregulated in both primary tumor specimens and cell lines whereas miR-140-5p was significantly downregulated. Ectopic expression of miR-140-5p markedly decreased SEPT2 protein concentration in BTC cells and suppressed cell proliferation and colony formation in vitro. Interaction between miR-140-5p and the 3'UTR of SEPT2 was confirmed by luciferase assays and rescue experiments. Furthermore, overexpression of SEPT2 and low expression of miR-140-5p were associated with increased invasion of BTC as indicated by clinical parameters and confirmed by invasion assays in vitro. Xenografts formation assay also showed that SEPT2 overexpression significantly facilitated the growth of tumor in vivo. This finding may provide a novel therapeutic strategy for the treatment of biliary tract cancer.
proteins
2026-01-10 | Epidemiological characterization of biliary tract cancer patients from the Spanish RETUD Registry.
503 Background: Biliary tract cancer (BTC) is a heterogeneous group of tumors, including cholangiocarcinoma (intra and extrahepatic) and gallbladder carcinoma (GC). We describe the epidemiology of BTC patients (pt) from the RETUD registry. Methods: We evaluated a large real-world cohort of pt diagnosed with BTC between January 1, 2017, and May 30, 2025. Analyses were based on first therapeutic approach as follows: resectable disease (RD) for patients with neoadjuvant/adjuvant therapy and/or radical treatment (surgery and/or locoregional therapy); and advanced disease (AD) for former patients who relapsed and those initially treated with first line therapy with/without other locoregional treatments. Analysis comprised demographic and clinical characteristics, tumor molecular profile, therapeutic procedures and efficacy outcomes (EO). Time to relapse (TTR) for RD, progression-free survival (PFS) for AD and overall survival (OS) for both were estimated using the Kaplan-Meier method. Results: A total of 1756 pt from 40 centers were classified as RD (695) or AD (1450). 389 (55,9%) pt were initially RD but progressed to AD. Median (m) age at diagnosis (dx) was 67.4 years (y), with 44.3% of women. Most frequent tumor locations at dx were intrahepatic (53.0%) and GC (15.5%). Distant metastasis in AD pt occurred primarily in liver (65.1%). 89.3% received chemotherapy, 10.7% were treated with immunotherapies, 6.3% received targeted therapies, and 7.7% of pt took part in at least one clinical trial. Biomarkers were determined in 553 pt (31.5%). ESCAT-I alterations were found in 176 pt (31.8%), most frequent ones are shown in table 1. RD pt: surgery was performed in 95.7%, locoregional therapy in 15.1% and 68.9% and 5.0% received adjuvant and neoadjuvant therapy respectively. With a m (p25, p75) follow-up of 23.9 months (mo) (14.4, 39.5), mOS was 33.0 mo (95% CI 30.2-38.9). mTTR was 19.4 mo (95% CI 17.3-22.2). AD pt: 1st and 2nd lines were administered to 96.4% and 42.6% pt. Most common schemes were CISGEM and FOLFOX, respectively. Thromboembolic events occurred in 17.3% of AD pt. With a m (p25, p75) follow-up of 13.2 mo (6.7, 22.9), mOS was 10.4 mo (95% CI 9.7-11.2). 1st line mPFS was 5.3 mo (95% CI 4.9-5.6). All pt: There were differences in mOS by age groups; 20.9 mo (95% CI 16.8-26.9) in <50 y pt vs 16.3 mo (95% CI 15.1-17.3) in ≥50 y pt (p=0.033); but not for sex; 16.3 mo (95% CI 14.9-17.9) in males vs 16.6 mo (95% CI 15.1-17.9) in females (p=0.444). Conclusions: This large multicenter real-world study provides a comprehensive characterization of BTC epidemiology in Spain. Treatment patterns observed, specifically those with IT and TT, reflect a progressive uptake of these innovative treatments in standard of care therapies. Most frequent ESCAT-I alterations. ESCAT-I Biomarker determination, N Alteration, N (%) IDH1 mutation 445 73 (16.4%) FGFR2 fusion 399 26 (6.5%) MSI 491 30 (6.1%) HER2 amplification/overexpression 448 24 (5.4%)
2024-04-12 | Unresectable biliary tract cancer: current and future systemic therapy
For decades, treatment of advanced biliary tract cancer (BTC) was confined to the use of chemotherapy. In recent years however, the number of therapeutic options available for patients with unresectable BTC have drastically increased, with immunotherapy and targeted treatment gradually joining the ranks of guideline-recommended treatment regimens. The aim of the present review is to summarise the current knowledge on unresectable BTC focusing on epidemiology, anatomical distribution and current strategies for systemic treatment. We further outline ongoing clinical trials and provide an outlook on future therapeutic interventions. In the realm of gastrointestinal malignancies, the increasing number of systemic treatment options for BTC is finally delivering on the longstanding commitment to personalised oncology. This emphasises the need for considering a comprehensive genomic-based pathology assessment right from the initial diagnosis to fully leverage the expanding array of therapeutic options that have recently become accessible.
2021-02-06 | The immunological characteristics of gallbladder carcinoma and advances in immunotherapy practices
Gallbladder carcinoma (GBC) is one of the most common malignant tumors in the biliary system, ranking sixth among gastrointestinal malignancies. In addition, the incidence of GBC has recently increased in China. GBC metastasizes early and invades adjacent organs such as the liver, making patients with GBC ineligible for radical surgery and giving them a poor prognosis. What is more, GBC is more inclined to develop chemo-resistance, which requires new strategies for clinical intervention. Cancer immunotherapy has made great advances over the past few years, with improved clinical efficacy against multiple malignancies, including GBC. This review summarizes the immunological characteristics of GBC as well as current advances in immunotherapies for GBC in order to provide new insights into future treatment and prevention of GBC.
2018-09-15 | Long-term survival of a patient with recurrent gallbladder carcinoma, treated with chemotherapy, immunotherapy, and surgery: a case report
Gallbladder cancer (GBC) is one of the refractory diseases. Multidisciplinary approach including immunotherapy for such cancers has received much attention in recent years. A 59-year-old man underwent an extended cholecystectomy for GBC (pathological stage II, T2 N0 M0, [per UICC 7th edition]) that was incidentally found during cholelithiasis surgery, and was then treated with adjuvant gemcitabine (GEM). Three months later, when a recurrence-suspected lesion was detected in segment 5 (S5) of his liver, we started adoptive immunotherapies with cytokine-activated killer (CAK) cell infusions, combined with chemotherapy. After a year of adjuvant immunochemotherapy, the S5 lesion disappeared on imaging, but lesions suspected metastatic recurrence again appeared in S7 and S8 at 4 years and 6 months post-surgery, for which GEM and cisplatin (CDDP) were administered as second-line chemotherapy. Immunochemotherapy produced stable disease (per RECIST) for 9 months, when tumor growth was detected; open microwave coagulo-necrotic therapy (MCN) was performed for these lesions. Three years after MCN, a solitary liver metastasis was detected in S4. MCN was conducted again, and peritoneal dissemination was found intraoperatively. A month after the second MCN, the patient’s carcinoembryonic antigen (CEA) level had increased. Therefore, GEM and tegafur-gimeracil-oteracil potassium (TS-1) were administered as third-line chemotherapy. We also switched the adoptive immunotherapy for tumor-associated antigen-pulsed dendritic cell-activated killer (DAK) cell immunotherapy. After nine courses of GEM and TS-1 administration, CEA had decreased to a normal level. At the time of reporting, 9 years and 6 months have passed since the initial surgery, and 18 months have passed since the peritoneal metastasis was detected. GEM and CDDP are currently administered as fourth-line chemotherapy because of re-increased CEA. Although an undeniable metastasis was found in his para-aortic lymph node, this patient visits our clinic regularly for immunotherapy. We here report a rare case of long-term survival of recurrent GBC well controlled by multidisciplinary therapy. Immunotherapy may be a promising modality among multidisciplinary methods for advanced cancer.
2017-11-01 | Immunotherapy as a treatment for biliary tract cancers: A review of approaches with an eye to the future
Biliary tract cancers (BTC) are aggressive malignancies associated with resistance to chemotherapy and poor prognostic rates. Therefore, novel treatment approaches are in need. Immunotherapy represents a promising breakthrough that uses a patient's immune system to target a tumor. This treatment approach has shown immense progress with positive results for selected cancers such as melanoma and nonsmall cell lung cancer. Initial preclinical data and preliminary clinical studies suggest encouraging mechanistic effects for immunotherapy in BTC offering the hope for an expanding therapeutic role for this disease. These approaches include targeted tumor antigen therapy via peptide and dendritic cell-based vaccines, allogenic cell adoptive immunotherapy, and the use of inhibitory agents targeting the immune checkpoint receptor pathway and multiple components of the tumor microenvironment. At this time demonstrating efficacy in larger clinical trials remains imperative. A multitude of ongoing trials aim to successfully translate mechanistic effects into antitumor efficacy and ultimately aim to incorporate immunotherapy into the routine management of BTC. With further research efforts, the optimization of dosing and therapeutic regimens, the identification of novel tumor antigens and a better understanding of alternative checkpoint pathway receptor expression may provide additional targets for rational combinatorial therapies which enhance the effects of immunotherapy and may offer hope for further advancing treatment options. Ultimately, the challenge remains to prospectively identify the subsets of patients with BTC who may respond to immunotherapy, and devising alternative strategies to sensitize those that do not with the hopes of improving outcomes for all with this deadly disease.
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2023-01-08 | Immune-Markers in GallBladder Lesions and their Clinico-Diagnostic and Prognostic Significance - An Overview
Gallbladder benign diseases are common and usually cured without further consequences.Some benign illnesses increase the chance of cancer development significantly, whereas others resemble malignant disorders.The biomarkers discussed thus far are among the most extensively researched concerning the different diseases of GBC.Patients with gallbladder cancer are usually diagnosed in later stages when conventional treatments are ineffective.The lack of responsiveness of advanced instances of GBC to existing therapies necessitates the identification of novel prognostic and therapeutic approaches.Novel prognostic biomarkers may provide a crucial breakthrough in this area.Despite the available data and years of research, a prognostic marker that is 100% specific and sensitive to GBC is not yet available.A diverse number of molecular markers have been studied for their potential to be prognostic markers in GBC.p53 and HER2 have been studied very extensively and have shown promise.The deregulation and accumulation of the molecular markers we have discussed so far impact carcinogenesis of the gall bladder.Further analytical studies on the concentration levels of these markers in normal vs precancerous vs cancerous tissues should be carried out.Highly specific prognostic markers can help individualize treatment options to bring down the mortality rate in GBC.
2020-10-17 | Oncogenic KRAS–expressing organoids with biliary epithelial stem cell properties give rise to biliary tract cancer in mice
Abstract Biliary tract cancer (BTC) arises from biliary epithelial cells (BECs) and includes intrahepatic cholangiocarcinoma (IHCC), gallbladder cancer (GC), and extrahepatic cholangiocarcinoma (EHCC). Although frequent KRAS mutations and epigenetic changes at the INK4A/ARF locus have been identified, the molecular pathogenesis of BTC is unclear and the development of corresponding anticancer agents remains inadequate. We isolated epithelial cell adhesion molecule (EpCAM)–positive BECs from the mouse intrahepatic bile duct, gallbladder, and extrahepatic bile duct, and established organoids derived from these cells. Introduction of activated KRAS and homozygous deletion of Ink4a/Arf in the cells of each organoid type conferred the ability to form lethal metastatic adenocarcinoma with differentiated components and a pronounced desmoplastic reaction on cell transplantation into syngeneic mice, indicating that the manipulated cells correspond to BTC–initiating cells. The syngeneic mouse models recapitulate the pathological features of human IHCC, GC, and EHCC, and they should therefore prove useful for the investigation of BTC carcinogenesis and the development of new therapeutic strategies. Tumor cells isolated from primary tumors formed organoids in three‐dimensional culture, and serial syngeneic transplantation of these cells revealed that their cancer stem cell properties were supported by organoid culture, but not by adherent culture. Adherent culture thus attenuated tumorigenic activity as well as the expression of both epithelial and stem cell markers, whereas the expression of epithelial‐mesenchymal transition (EMT)–related transcription factor genes and mesenchymal cell markers was induced. Our data show that organoid culture is important for maintenance of epithelial cell characteristics, stemness, and tumorigenic activity of BTC–initiating cells.
2019-07-02 | Establishment of an organoid bank of biliary tract and pancreatic cancers and its application for personalized therapy and future treatment
Abstract Biliary tract cancers and pancreatic cancers are aggressive malignancies that are difficult to diagnose early and have a poor prognosis. Patients with inoperable biliary tract and pancreatic cancers generally receive chemotherapy regimens including gemcitabine. However, the effects of these drugs are limited, and the 5‐year survival rates of patients are very low. The newly developed three‐dimensional culture system known as “organoid culture” allows long‐term expansion of stem cells into cyst‐like structures (organoids) with properties resembling those of the original tissues. We and other groups have successfully established long‐term in vitro cultures of organoids derived from biliary tract and pancreatic cancers. Organoids derived from biliary tract and pancreatic cancers closely recapitulate the properties of the original tumors including genetic alterations, gene expression profiles, and histopathological structures. These patient‐derived cancer organoids can be applied for drug sensitivity testing, drug screening, epigenetic therapy, and differentiation‐inducing therapy to identify therapeutic agents optimal for each patient. We intend to further establish organoids derived from various cancer cases and construct an organoid bank of biliary tract and pancreatic cancers. These powerful in vitro preclinical models of refractory cancers may bridge the gap between basic research and clinical trials and allow personalized therapy for patients.
2017-04-01 | Mesothelin-targeting chimeric antigen receptor-modified T cells by piggyBac transposon system suppress the growth of bile duct carcinoma.
Chimeric antigen receptor modified T cell–based immunotherapy is revolutionizing the field of cancer treatment. However, its potential in treating bile duct carcinoma has not been fully explored. Herein, we developed the second-generation mesothelin-targeting chimeric antigen receptor–modified T cells with the 4-1BB co-stimulatory module by the piggyBac transposon system. Mesothelin-targeting chimeric antigen receptor was expressed by 66.0% of mesothelin-targeting chimeric antigen receptor–modified T cells post electrophoretic transfection and stimulation with K562-meso cells; the expressions of activation markers were tested by flow cytometry assay and showed greater activation of mesothelin-targeting chimeric antigen receptor–modified T cells than control T cells (CD107α: 71.9% vs 48.6%; CD27: 92.1% vs 61.8%; CD137: 55.5% vs 8.4%; CD28: 98.0% vs 82.1%; CD134: 37.5% vs 10.4%). Furthermore, mesothelin-targeting chimeric antigen receptor–modified T cells exerted cytotoxicity toward mesothelin-expressing EH-CA1b and EH-CA1a cells in an effector-to-target ratio-dependent manner, while leaving mesothelin-negative GSC-SD and EH-GB1 cells and normal liver L02 cells almost unharmed. Mesothelin-targeting chimeric antigen receptor–modified T cells secreted cytokines at higher levels when co-cultured with mesothelin-positive EH-CA1a and EH-CA1b cells than with mesothelin-negative GSC-SD and EH-GB1 cells. Enhanced cytotoxicity and cytokine secretion of mesothelin-targeting chimeric antigen receptor–modified T cells compared to control T cells were also observed when co-cultured with 293-meso cells (interferon γ: 85.1% ± 1.47% vs 8.3% ± 2.50%, p = 0.000; tumor necrosis factor α: 90.9% ± 4.67% vs 18.5% ± 3.62%, p = 0.0004; interleukin 2: 60.8% ± 2.00% vs 15.6% ± 2.06%, p = 0.002; interleukin 6: 6.4% ± 2.95% vs 1.7% ± 0.63%, p = 0.055). In addition, mesothelin-targeting chimeric antigen receptor–modified T cells showed greater inhibitory and proliferative capability than control T cells within EH-CA1a cell xenografts. This study shows the potential of mesothelin-targeting chimeric antigen receptor–modified T cells in treating bile duct carcinoma.
2014-08-22 | Retrohepatic inferior vena cava reconstruction with saphenous vein patch in advanced stage cholangiocarcinoma
Hepatic resection is the only known curative treatment option in primary and metastatic liver tumors. Unlike other types of malignancies, the response rate to even the best chemotherapy protocols is quite low in liver malignancies. Survival is expressed in months in untreated liver malignancies or in patients with residual tumor after resection. The optimal survival can be achieved only by liver resection with negative surgical margins. In order to increase the number of patients suitable for hepatic resection, techniques such as portal vein embolization, neoadjuvant chemotherapy, two-step hepatectomy, re-do hepatectomy, hypothermic liver perfusion have been developed and newer modalities are still being investigated. Primary liver malignancies like hepatocellular carcinoma and cholangiocarcinoma, and metastatic liver tumors can invade the retrohepatic vena cava due to anatomical proximity. Invasion of either the hepatocaval confluence or vena cava are often considered as contraindications for liver resection due to the risk of intraoperative massive air embolism or hemorrhage. In this article, we present a patient who underwent left hepatectomy together with vena cava resection and reconstruction with saphenous vein patch due to cholangiocarcinoma.
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Drug Discovery Landscape
32 orphan drug designations for Carcinoma of gallbladder and extrahepatic biliary tract, including 6 approved therapies.
32 orphan drug designations for Carcinoma of gallbladder and extrahepatic biliary tract, including 6 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
gemcitabine liposome injection | small molecules | FDA | 2025-07-01 | — | FUJIFILM Pharmaceuticals U.S.A., Inc. |
Tinengotinib | small molecules | EMA | 2024-02-19 | — | Parexel International (IRL) Limited |
an antibody-drug conjugate (ADC) consisting of a humanized anti-HER2 IgG1 monoclonal antibody (SHR-1805) linked with SHR169106. The active toxin ingredient SHR169265 (also named 9106-IM-2) is hydrolyzed at site 2 following enzymatic hydrolysis. The average drug antibody conjugation ratio (DAR) of SHR-A1811 is 5.3-6.1. | antibodies | FDA | 2023-12-14 | — | eVenus Pharmaceutical Lab Inc. |
small molecule PRMT5/MTA cooperative inhibitor | small molecules | FDA | 2023-11-28 | — | Amgen Inc. |
Spiro[3H-Indole-3,2¿-pyrrolidin]-2(1H)-one derivative | small molecules | FDA | 2023-06-08 | — | Boehringer Ingelheim Pharmaceuticals, Inc. |
Mefuparib Hydrochloride Tablets | small molecules | FDA | 2023-02-28 | — | Convalife (Shanghai) Co., Ltd. |
N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide hydrochloride | small molecules | EMA | 2022-11-10 | — | Elevar Therapeutics |
Nanvuranlat | small molecules | FDA | 2022-04-19 | — | J-Pharma Co., Ltd. |
Devimistat | small molecules | EMA | 2022-04-13 | — | IQVIA RDS Ireland Limited |
Silmitasertib | small molecules | FDA | 2022-01-19 | — | Senhwa Biosciences, Inc. |
Zanidatamab [Ziihera] | antibodies | EMA | 2021-07-19 | 2025-06-30 | Jazz Pharmaceuticals Ireland Limited |
durvalumab [Imfinzi] | antibodies | FDA | 2020-12-10 | 2022-09-02 | AstraZeneca Pharmaceuticals LP |
Fosgemcitabine palabenamide | small molecules | EMA | 2020-03-24 | — | Pharma Gateway AB |
Envafolimab | antibodies | FDA | 2020-01-16 | — | 3D Medicines (Sichuan) Co., Ltd |
zanidatamab-hrii [Ziihera] | antibodies | FDA | 2019-12-18 | 2024-11-20 | Jazz Pharmaceuticals Ireland Limited |
pembrolizumab [Keytruda] | antibodies | FDA | 2019-10-09 | 2023-10-31 | MSD International Business GmbH |
fosgemcitabine palabenamide | small molecules | FDA | 2019-06-11 | — | NuCana plc |
Futibatinib [Lytgobi] | small molecules | EMA | 2019-04-01 | — | Taiho Pharma Netherlands B.V. |
etoposide toniribate | small molecules | FDA | 2019-02-11 | — | CellAct Pharma GmbH |
Bintrafusp alfa | proteins | EMA | 2018-12-14 | — | Merck Europe B.V. |
Sodium 2-hydroxylinoleate | small molecules | EMA | 2018-12-14 | — | Ability Pharmaceuticals SL |
sodium 2-hydroxylinoleate | small molecules | FDA | 2018-09-27 | — | Ability Pharmaceuticals, SL |
Pemigatinib [Pemazyre] | small molecules | EMA | 2018-08-24 | 2021-03-29 | Incyte Biosciences Distribution B.V. |
Ivosidenib [Tibsovo] | small molecules | EMA | 2018-03-21 | 2023-05-08 | Les Laboratoires Servier |
Zoligratinib [Debio 1347] | small molecules | EMA | 2017-10-16 | — | Voisin Consulting Life Sciences |
Cis-diamminedichloroplatinum (II) polyethylene glycol-polyglutamate (cis platinum PEG-pGlu) polymeric micelles | small molecules | FDA | 2017-07-27 | — | NanoCarrier Co., Ltd |
merestinib | small molecules | FDA | 2017-04-10 | — | Eli Lilly and Company |
(R)-6-(2-fluorophenyl)-N-(3-(2-((2-methoxyethyl)amino)ethyl)phenyl)-5,6-dihydrobenzo[h]quinazolin-2-amine dihydrochloride | small molecules | EMA | 2016-05-30 | — | Basilea Pharmaceutica Deutschland GmbH |
varlitinib | small molecules | FDA | 2015-08-05 | — | ASLAN Pharmaceuticals Pte, Ltd. |
5,10,15,20-tetrakis(2,6-difluoro-3-N-methylsulfamoylphenyl)bacteriochlorin | small molecules | EMA | 2015-03-19 | — | Luzitin S.A |
(5R,5aR,8aR,9S)-9-[[4,6-O-[(R)-Ethylidene]-beta-D-glucopyranosyl]-oxy]-5-(4-({[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]carbonyl}oxy)-3,5-dimethoxyphenyl)-5,8,8a,9-tetrahydroisobenzofuro[5,6-f][1,3]benzodioxol-6(5aH)-one | small molecules | EMA | 2014-06-04 | — | CellAct Pharma GmbH |
Becatecarin | small molecules | EMA | 2006-07-25 | — | Helsinn Birex Pharmaceuticals Limited |
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