Sorafenib in unresectable intrahepatic cholangiocellular carcinoma: a case report

Pinter, Matthias; Reisegger, Michael; Wrba, Friedrich; Peck‐Radosavljevic, Markus

doi:10.1007/s00508-010-1522-y

Cited by 11 publications

(8 citation statements)

References 23 publications

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“…The high proportion of genetic alterations in critical signaling pathways involved in cell proliferation in CCA has led to an interest in the development of clinical trials investigating targeted therapies including sorafenib . However, data on the effectiveness of sorafenib, and other TKIs, in patients with CCA are controversial, reporting both beneficial effect and poor activity against this type of liver cancer . The latter is not surprising considering the strong multidrug resistance (MDR) phenotype of CCA, in which several MOCs involved in the lack of response to sorafenib have been identified .…”

Section: Discussionmentioning

confidence: 99%

Causes of hOCT1‐Dependent Cholangiocarcinoma Resistance to Sorafenib and Sensitization by Tumor‐Selective Gene Therapy

et al. 2019

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Although the multi-tyrosine kinase inhibitor sorafenib is useful in the treatment of several cancers, cholangiocarcinoma (CCA) is refractory to this drug. Among other mechanisms of chemoresistance, impaired uptake through human organic cation transporter type 1 (hOCT1) (gene SLC22A1) has been suggested. Here we have investigated the events accounting for this phenotypic characteristic and have evaluated the interest of selective gene therapy strategies to overcome this limitation. Gene expression and DNA methylation of SLC22A1 were analyzed using intrahepatic (iCCA) and extrahepatic (eCCA) biopsies (Copenhagen and Salamanca cohorts; n = 132) and The Cancer Genome Atlas (TCGA)-CHOL (n = 36). Decreased hOCT1 mRNA correlated with hypermethylation status of the SLC22A1 promoter. Treatment of CCA cells with decitabine (demethylating agent) or butyrate (histone deacetylase inhibitor) restored hOCT1 expression and increased sorafenib uptake. MicroRNAs able to induce hOCT1 mRNA decay were analyzed in paired samples of TCGA-CHOL (n = 9) and Copenhagen (n = 57) cohorts. Consistent upregulation in tumor tissue was found for miR-141 and miR-330. High proportion of aberrant hOCT1 mRNA splicing in CCA was also seen. Lentiviral-mediated transduction of eCCA (EGI-1 and TFK-1) and iCCA (HuCCT1) cells with hOCT1 enhanced sorafenib uptake and cytotoxic effects. In chemically induced CCA in rats, reduced rOct1 expression was accompanied by impaired sorafenib uptake. In xenograft models of eCCA cells implanted in mouse liver, poor response to sorafenib was observed. However, tumor growth was markedly reduced by cotreatment with sorafenib and adenoviral vectors encoding hOCT1 under the control of the BIRC5 promoter, a gene highly up-regulated in CCA. Conclusion: The reason for impaired hOCT1-mediated sorafenib uptake by CCA is multifactorial. Gene therapy capable of selectively inducing hOCT1 in tumor cells can be considered a potentially useful chemosensitization strategy to improve the response of CCA to sorafenib. (Hepatology 2019;70:1246-1261).

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Section: Discussionmentioning

confidence: 99%

Causes of hOCT1‐Dependent Cholangiocarcinoma Resistance to Sorafenib and Sensitization by Tumor‐Selective Gene Therapy

et al. 2019

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“…interventional treatments, radiation, chemotherapy) can be applied (4,(8)(9)(10). Molecular targeted treatment with sorafenib has shown some efficacy in several case reports (11)(12)(13) but failed to improve survival in larger phase II studies (14,15).…”

Section: Introductionmentioning

confidence: 99%

Incidence and mortality trends for biliary tract cancers in Austria

Pinter

Hucke

Zielonke

et al. 2013

Liver International

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“…In a retrospective review where patients with unresectable iCCA were exposed to multiple lines of chemotherapy, patients had a median OS of 27.7 months . In general, median OS after systemic chemotherapy ranged from 5.2 months to 15.7 months from time of initial treatment .…”

Section: Methodsmentioning

confidence: 99%

Multimodality treatment of intrahepatic cholangiocarcinoma: A review

Simo

Halpin

McBrier

et al. 2016

Journal of Surgical Oncology

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Sorafenib in unresectable intrahepatic cholangiocellular carcinoma: a case report

Abstract: Sorafenib was effective and well-tolerated in a patient with advanced cholangiocellular carcinoma. Prospective trials are warranted to evaluate the benefit of sorafenib in unresectable CCC.

Cited by 11 publications

References 23 publications

Causes of hOCT1‐Dependent Cholangiocarcinoma Resistance to Sorafenib and Sensitization by Tumor‐Selective Gene Therapy

Causes of hOCT1‐Dependent Cholangiocarcinoma Resistance to Sorafenib and Sensitization by Tumor‐Selective Gene Therapy

Incidence and mortality trends for biliary tract cancers in Austria

Multimodality treatment of intrahepatic cholangiocarcinoma: A review

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