Molecular Targets in Biliary Carcinogenesis and Implications for Therapy

Oyasiji, Tolutope; Zhang, Jianliang; Kuvshinoff, Boris W.; Iyer, Renuka; Hochwald, Steven N.

doi:10.1634/theoncologist.2014-0442

Cited by 13 publications

(12 citation statements)

References 104 publications

(112 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since the prognosis of CCA remains poor with traditional chemotherapy, in the era of personalized medicine several research teams have been working on the molecular and genetic characterization of CCA to identify molecular targets (5)(6)(7)(8)14). Landscape of signalling pathways offers multiple therapeutic targets including growth factor receptors (GFRs) like epidermal (EGFR), vascular (VEGFR), human epidermal growth factor receptor 2 (HER2), the ligand of VEGFR (VEGF) and their downstreaming signal molecules of RAS-RAF-MEK-ERK and PI3K-ACT-mTOR (5)(6)(7)(8)14). Targetspecific monoclonal antibodies and tyrosine kinase inhibitors are able to block selectively the over-expressed or over-activated signal molecules potentiating the growth and invasion of CCA cells.…”

Section: Discussionmentioning

confidence: 99%

“…In CCA the frequency of BRAF V600E has been reported to range 0-12% in EH and 0-22% in IH subtypes (5)(6)(7)(8)14). Although BRAF V600 can serve as a potential molecular target in CCA, until now there was no evidence of benefit using BRAF inhibitor therapy.…”

Section: Discussionmentioning

confidence: 99%

“…Due to the dismal prognosis with conventional chemotherapy, attention has been shifting to the potential role of molecularly targeted agents in advanced CCA. Several clinical trials had been carried out, where targeted agents were applied alone or in combination with chemotherapy with only modest or no proven benefit at all (5)(6)(7)(8). One main limitation of most trial design was subject heterogeneity with regards to the anatomical and molecular characteristics of the cholangiocellular malignancies.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Combined dabrafenib and trametinib treatment in a case of chemotherapy-refractory extrahepatic BRAF V600E mutant cholangiocarcinoma: dramatic clinical and radiological response with a confusing synchronic new liver lesion

Kocsis

Árokszállási

András

et al. 2017

J. Gastrointest. Oncol.

View full text Add to dashboard Cite

Since the prognosis of advanced cholangiocarcinoma (CCA) remains poor with traditional chemotherapy, attention has shifted to molecularly targeted agents. Results of available clinical studies reveal little or no benefit of using targeted agents in advanced CCA. Limitations of these trials could be the lack of comprehensive molecular and genetic characterization of CCA samples in order to identify potential drug targets. Here we report a case of a 59-year-old female with chemotherapy-refractor, metastatic extrahepatic cholangiocarcinoma (EHCCA). After failure of first-line chemotherapy with cisplatin plus gemcitabine, next generation sequencing (NGS) based tumor molecular profiling was performed on aspiration cytological sample, that revealed BRAF V600E mutation. Multidisciplinary team decided on the initiation of combined treatment with BRAF and MEK inhibitors. Dabrafenib was started orally 150 mg twice a day, adding trametinib 2 mg once a day. Right from the initiation of targeted therapy, significant clinical improvement had been observed. Even though the first restaging computed tomography (CT) scan at 8 weeks revealed spectacular decrease in all metastatic sites, a new hepatic mass of 67 mm × 40 mm was identified and interpreted as new metastatic lesion. As the clinical and radiological response was contradictory, CT-guided biopsy was taken from the hepatic lesion while the therapy was continued on. Histopathologic evaluation excluded the hepatic lesion from being a metastasis, instead described it as a fibrotic, inflammatory lesion.At 12 week, PET CT confirmed further tumor regression with complete regression of the multiple cerebral metastases. The therapy has been extremely well tolerated by the patient. According to our knowledge, this is the first reported case on a successful treatment of EHCCA with the combination of dabrafenib and trametinib. Our case highlights the importance of molecular profiling in CCA, in order to find potential actionable driver mutations for personalised treatment.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Combined dabrafenib and trametinib treatment in a case of chemotherapy-refractory extrahepatic BRAF V600E mutant cholangiocarcinoma: dramatic clinical and radiological response with a confusing synchronic new liver lesion

Kocsis

Árokszállási

András

et al. 2017

J. Gastrointest. Oncol.

View full text Add to dashboard Cite

show abstract

“…Even amongst those able to undergo radical resection, the recurrence risk is high and the 5-year overall survival is only 30% [3]. One of the first-line chemotherapeutic agents, cisplatin, has been universally found to benefit individuals with advanced, unresectable or metastatic gallbladder cancer [4, 5]. The current standard first-line treatment for unresectable CCA is combination treatment with gemcitabine and cisplatin, however, drug resistance is common and the prognosis of patients is universally poor [6].…”

Section: Introductionmentioning

confidence: 99%

MiR-199a-3p enhances cisplatin sensitivity of cholangiocarcinoma cells by inhibiting mTOR signaling pathway and expression of MDR1

Xia

et al. 2017

Oncotarget

View full text Add to dashboard Cite

Several studies have reported reduced miRNA-199a-3p (miR-199a-3p) in different human malignancies, however, little is known about miR-199a-3p in cholangiocarcinoma cells. In this study, we demonstrate the essential role and mechanism of miR-199a-3p in regulating cisplatin sensitivity in cholangiocarcinoma cell lines. Using a CCK-8 cell counting assay we found that expression of miR-199a-3p was positively correlated with cisplatin sensitivity in cholangiocarcinoma cell lines. MiR-199a-3p overexpression could decrease the proliferation rate and increase apoptosis of cholangiocarcinoma cells in the presence of cisplatin, while miR-199a-3p inhibition had the opposite effect. Further study demonstrated that mTOR was the target gene of miR-199a-3p, and that miR-199a-3p mimics could inhibit expression of mTOR, which consequently reduced the phosphorylation of its downstream proteins 4EBP1 and p70s6k. Rescue experiments proved that miR-199a-3p could increase the cisplatin sensitivity of cholangiocarcinoma cell lines by regulating mTOR expression. Moreover, we also found that miR-199a-3p overexpression could reduce cisplatin induced MDR1 expression by decreasing the synthesis and increasing the degradation of MDR1, thus enhancing the effectiveness of cisplatin in cholangiocarcinoma. In conclusion, miR-199a-3p could increase cisplatin sensitivity of cholangiocarcinoma cell lines by inhibiting the activity of the mTOR signaling pathway and decreasing the expression of MDR1.

show abstract

“…For example, Yoshikawa et al reported that the epidermal growth factor receptor overexpression was associated with lymph node metastasis, lymphatic vessel invasion and perineural invasion in extrahepatic CCA, and vascular endothelial growth factor overexpression with intrahepatic metastasis in intrahepatic CCA [ 8 ]. In addition, several studies have indicated that epigenetic modifications of genes involved in progression turned out to be another possible mechanism underlying CCA metastasis [ 9 ]. For instance, E-cadherin promoter methylation was found to be associated with increased migration and invasion in CCA [ 9 – 14 ].…”

Section: Introductionmentioning

confidence: 99%

Adipocytes promote cholangiocarcinoma metastasis through fatty acid binding protein 4

Nie

Zhang

Wang

et al. 2017

J Exp Clin Cancer Res

View full text Add to dashboard Cite

BackgroundThe early occurrence regional nodal and distant metastases cholangiocarcinoma (CCA) is one of the major reasons for its poor prognosis. However, the related mechanisms are largely elusive. Recently, increasing evidences indicate that adipocytes might be involved in the proliferation, homing, migration and invasion of several malignancies. In the present study, we attempt to determine the effects and possible mechanisms of adipocytes on regulating progression of CCA.MethodsAdipocyte–CCA cell co-culture system and CCA metastasis mice model were used to determine the effects of adipocytes on CCA metastasis. We identified the biological functions and possible mechanisms of adipocyte-derived fatty acid binding protein 4 (FABP4) in regulating the adipocyte-induced CCA metastasis and epithelial-mesenchymal transition (EMT) phenotypes, both in vitro and in vivo.ResultsAdipocyte–CCA cell co-culture promotes the in vitro and in vivo tumor metastasis, leading to increased adipocyte-derived fatty acid absorbance and intracellular lipids of CCA cells, which indicates adipocytes might function as the energy source for CCA progression by providing free fatty acids. Further, highly expressed FABP4 protein was identified in adipose tissues and fully differentiated adipocytes, and upregulated FABP4 was also detected by qRT-PCR assay in CCA cells co-cultivated with adipose extracts as compared to parental CCA cells. The specific FABP4 inhibitor BMS309403 significantly impaired adipocyte-induced CCA metastasis and EMT phenotypes both in vitro and in vivo.ConclusionsTogether, the results demonstrate that the adipocyte-CCA interaction and the energy extraction of CCA cells from adipocytes are crucial for the invasion, migration and EMT of CCA cells. FABP4 from adipocytes mediates these adipocyte-induced variations in CCA cells, which could serve as a potential target for the treatment of CCA.Electronic supplementary materialThe online version of this article (10.1186/s13046-017-0641-y) contains supplementary material, which is available to authorized users.

show abstract

Molecular Targets in Biliary Carcinogenesis and Implications for Therapy

Cited by 13 publications

References 104 publications

Combined dabrafenib and trametinib treatment in a case of chemotherapy-refractory extrahepatic BRAF V600E mutant cholangiocarcinoma: dramatic clinical and radiological response with a confusing synchronic new liver lesion

Combined dabrafenib and trametinib treatment in a case of chemotherapy-refractory extrahepatic BRAF V600E mutant cholangiocarcinoma: dramatic clinical and radiological response with a confusing synchronic new liver lesion

MiR-199a-3p enhances cisplatin sensitivity of cholangiocarcinoma cells by inhibiting mTOR signaling pathway and expression of MDR1

Adipocytes promote cholangiocarcinoma metastasis through fatty acid binding protein 4

Contact Info

Product

Resources

About