Identification of Active Chemotherapy Regimens in Advanced Biliary Tract Carcinoma: A Review of Chemotherapy Trials in the past Two Decades

Ulahannan, Susanna; Rahma, Osama E.; Duffy, Austin G.; Makarova-Rusher, Oxana V.; Kurtoğlu, Metin; Liewehr, David J.; Steinberg, Seth M.; Greten, Tim F.

doi:10.2217/hep.14.36

Cited by 10 publications

(6 citation statements)

References 93 publications

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“…CCC is a highly lethal cancer due to lack of early detection, resistance to chemoradiotherapy and high propensity to invade locally and distantly ( 25 ). Current therapeutic approaches for highly invasive cholangiocarcinoma are not very effective ( 26 ). The low overall survival rate of CCC has led investigators to investigate the mechanisms involved in the characteristic development and progression of CCC to identify effective therapeutic methods.…”

Section: Discussionmentioning

confidence: 99%

HOXD10 acts as a tumor-suppressive factor via inhibition of the RHOC/AKT/MAPK pathway in human cholangiocellular carcinoma

Yang

Zhou

et al. 2015

Oncology Reports

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HOXD10, a key regulator of cell-differentiated phenotype maintainence, has been demonstrated to be involved in the tumorigenesis of many human malignacies. However, the status of HOXD10 expression and its biological function in cholangiocellular carcinoma (CCC) remain to be clarified. In the present study, we investigated the clinical significance and biological functions of HOXD10 in CCC and found that the expression of HOXD10 and its downstream effector RHOC was significantly different in well-differentiated CCC tissues compared with poorly-differentiated lesions. We also observed a significant correlation between low HOXD10 and high RHOC expression levels and worse prognosis. The stable overexpression of HOXD10 by lentivirus vector significantly inhibited cell invasion partly by downregulating the expression of MMP2 and MMP9, and significantly increased early apoptosis in CCC cell lines and induced G1 phase cell cycle arrest, contributing to the inhibition of cell proliferation in vitro. Additionally, we demonstrated that the inactivation of the RHOC/AKT/MAPK pathway was involved in the tumor-suppressive functions of HOXD10 in CCC. These results suggested that HOXD10 may be a putative suppressor gene and can act as a prognostic marker and potentially a novel therapeutic target for CCC.

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Section: Discussionmentioning

confidence: 99%

HOXD10 acts as a tumor-suppressive factor via inhibition of the RHOC/AKT/MAPK pathway in human cholangiocellular carcinoma

Yang

Zhou

et al. 2015

Oncology Reports

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“…Chronic inflammation processes, such as cholangitis/primary sclerosing cholangitis (PSC), secondary biliary cirrhosis, choledocholithiasis, hepatolithiasis, cholecystitis, as well as HCV and HBV infections promote ICC arising and progression [ 3 – 6 ]. Conventional chemotherapy, based on combination of gemcitabine (GEM) and platinum compounds, and radiotherapy, to date, are not effective in improving long-term survival [ 7 , 8 ]. Moreover, primary or acquired resistance is inevitable and no second-line chemotherapy has demonstrated efficacy.…”

Section: Introductionmentioning

confidence: 99%

Transcriptomic analysis and mutational status of IDH1 in paired primary-recurrent intrahepatic cholangiocarcinoma

et al. 2018

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BackgroundEffective target therapies for intrahepatic cholangiocarcinoma (ICC) have not been identified so far. One of the reasons may be the genetic evolution from primary (PR) to recurrent (REC) tumors. We aim to identify peculiar characteristics and to select potential targets specific for recurrent tumors.Eighteen ICC paired PR and REC tumors were collected from 5 Italian Centers. Eleven pairs were analyzed for gene expression profiling and 16 for mutational status of IDH1. For one pair, deep mutational analysis by Next Generation Sequencing was also carried out. An independent cohort of patients was used for validation.ResultsTwo class-paired comparison yielded 315 differentially expressed genes between REC and PR tumors. Up-regulated genes in RECs are involved in RNA/DNA processing, cell cycle, epithelial to mesenchymal transition (EMT), resistance to apoptosis, and cytoskeleton remodeling. Down-regulated genes participate to epithelial cell differentiation, proteolysis, apoptotic, immune response, and inflammatory processes. A 24 gene signature is able to discriminate RECs from PRs in an independent cohort; FANCG is statistically associated with survival in the chol-TCGA dataset. IDH1 was mutated in the RECs of five patients; 4 of them displayed the mutation only in RECs. Deep sequencing performed in one patient confirmed the IDH1 mutation in REC.ConclusionsRECs are enriched for genes involved in EMT, resistance to apoptosis, and cytoskeleton remodeling. Key players of these pathways might be considered druggable targets in RECs. IDH1 is mutated in 30% of RECs, becoming both a marker of progression and a target for therapy.Electronic supplementary materialThe online version of this article (10.1186/s12864-018-4829-0) contains supplementary material, which is available to authorized users.

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“…The combination of gemcitabine and cisplatin chemotherapy has become the standard first‐line treatment regimen for advanced BTC, with a median survival of 11.7 months . For patients who progress on first‐line therapy, there is no standard second‐line option . Frequently, the chemotherapy regimens used are extrapolated from data in pancreatic and other gastrointestinal cancers with limited or uncertain benefit.…”

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confidence: 99%

Tremelimumab in Combination With Microwave Ablation in Patients With Refractory Biliary Tract Cancer

et al. 2019

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Treatment options for patients with advanced biliary tract cancer are limited. Dysregulation of the immune system plays an important role in the pathogenesis of biliary tract cancer (BTC). This study aimed to investigate whether tremelimumab, an anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4) inhibitor, could be combined safely with microwave ablation to enhance the effect of anti-CTLA4 treatment in patients with advanced BTC. Patients were enrolled to receive monthly tremelimumab (10 mg/kg, intravenously) for six doses, followed by infusions every 3 months until off-treatment criteria were met. Thirty-six days after the first tremelimumab dose, patients underwent subtotal microwave ablation. Interval imaging studies were performed every 8 weeks. Adverse events (AEs) were noted and managed. Tumor and peripheral blood samples were collected to perform immune monitoring and whole-exome sequencing (WES). Twenty patients with refractory BTC were enrolled (median age, 56.5 years). No dose-limiting toxicities were encountered. The common treatment-related AEs included lymphopenia, diarrhea, and elevated transaminases. Among 16 patients evaluable for efficacy analysis, 2 (12.5%) patients achieved a confirmed partial response (lasting for 8.0 and 18.1 months, respectively) and 5 patients (31.3%) achieved stable disease. Median progression free survival (PFS) and overall survival (OS) were 3.4 months (95% confidence interval [CI], 2.5-5.2) and 6.0 months (95% CI, 3.8-8.8), respectively. Peripheral blood immune cell subset profiling showed increased circulating activated human leukocyte antigen, DR isotype ([HLA-DR] positive) CD8 + T cells. T-cell receptor (TCR)β screening showed tremelimumab expanded TCR repertoire, but not reaching statistical significance (P = 0.057). Conclusion: Tremelimumab in combination with tumor ablation is a potential treatment strategy for patients with advanced BTC. Increased circulating activated CD8 + T cells and TCR repertoire expansion induced by tremelimumab may contribute to treatment benefit. (Hepatology 2019;69:2048-2060).

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Identification of Active Chemotherapy Regimens in Advanced Biliary Tract Carcinoma: A Review of Chemotherapy Trials in the past Two Decades

Cited by 10 publications

References 93 publications

HOXD10 acts as a tumor-suppressive factor via inhibition of the RHOC/AKT/MAPK pathway in human cholangiocellular carcinoma

HOXD10 acts as a tumor-suppressive factor via inhibition of the RHOC/AKT/MAPK pathway in human cholangiocellular carcinoma

Transcriptomic analysis and mutational status of IDH1 in paired primary-recurrent intrahepatic cholangiocarcinoma

Tremelimumab in Combination With Microwave Ablation in Patients With Refractory Biliary Tract Cancer

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