Targeted therapy for biliary tract cancers

Faris, Jason E.; Zhu, Andrew X.

doi:10.1007/s00534-011-0496-0

Cited by 26 publications

(22 citation statements)

References 79 publications

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“…The Advanced Biliary Cancer (ABC)-02 study showed that systemic combination chemotherapy of gemcitabine and cisplatin prolonged the survival of patients with inoperable cholangiocarcinoma, making it a treatment standard, and gemcitabine is still the key drug used in chemotherapy of advanced cholangiocarcinoma (39,40). In the present study, we demonstrated that the combination of DZNep and gemcitabine has a synergistic effect on two representative cholangiocarcinoma cell lines, RBE and TFK-1.…”

Section: Kip1mentioning

confidence: 58%

Epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin A inhibits the growth of cholangiocarcinoma cells

et al. 2013

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Abstract. Enhancer of zeste homolog 2 (EZH2) is involved in malignant transformation and the biological aggressiveness of several human malignancies. Growing evidence indicates that EZH2 may be an appropriate therapeutic target for malignancies, including cholangiocarcinoma. Recently, an S-adenosyl-L-homocysteine hydrolase inhibitor, 3-deazaneplanocin A (DZNep) was shown to deplete and inhibit EZH2. The aim of this study was to determine the effect of DZNep and the combination of gemcitabine and DZNep in cholangiocarcinoma cells. The effects of DZNep and its combination with gemcitabine were assessed in the cholangiocarcinoma cell lines RBE and TFK-1. DZNep depleted the cellular levels of EZH2 and inhibited the associated histone H3 lysine 27 trimethylation. DZNep treatment resulted in the inhibition of proliferation in the cholangiocarcinoma cell lines, and the combination of DZNep and gemcitabine showed synergistic inhibition of cell proliferation. DZNep induced apoptosis and G1 phase cell cycle arrest in cholangiocarcinoma cells, and the combination of DZNep and gemcitabine enhanced the induced apoptosis and G1 arrest when compared with gemcitabine alone. Inhibition of cell proliferation by DZNep was partially associated with upregulation of p16INK4a and p17 KIP1. The present study shows that DZNep inhibits cell proliferation by inducing G1 arrest and apoptosis. These results indicate that an epigenetic therapy that pharmacologically targets EZH2 via DZNep may constitute a novel approach for the treatment of cholangiocarcinoma.

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Section: Kip1mentioning

confidence: 58%

Epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin A inhibits the growth of cholangiocarcinoma cells

et al. 2013

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“…To date, clinical trials with targeted therapies for advanced biliary tract cancers have failed to produce significant benefits [11], and ongoing studies are exploring the combination of chemotherapy with novel MAPK/ERK Kinase (MEK) and mTOR inhibitors [40]. However, neither previous nor ongoing studies have considered evaluating tumour response against genetic alterations.…”

Section: Discussionmentioning

confidence: 99%

“…KRAS / NRAS / BRAF mutations were mutually exclusive, and the highest mutation prevalence in RAS pathway was observed in ECC (49.1%) vs. ICC (27.1%) and GBC (19.2%). Of note, RAS mutations sensitize tumours to MEK inhibitors, highlighting the importance of these mutations in the use of targeted therapies [11, 40]. …”

Section: Discussionmentioning

confidence: 99%

Multigene mutational profiling of cholangiocarcinomas identifies actionable molecular subgroups

Simbolo¹,

Fassan²,

et al. 2014

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One-hundred-fifty-three biliary cancers, including 70 intrahepatic cholangiocarcinomas (ICC), 57 extrahepatic cholangiocarcinomas (ECC) and 26 gallbladder carcinomas (GBC) were assessed for mutations in 56 genes using multigene next-generation sequencing. Expression of EGFR and mTOR pathway genes was investigated by immunohistochemistry. At least one mutated gene was observed in 118/153 (77%) cancers. The genes most frequently involved were KRAS (28%), TP53 (18%), ARID1A (12%), IDH1/2 (9%), PBRM1 (9%), BAP1 (7%), and PIK3CA (7%). IDH1/2 (p=0.0005) and BAP1 (p=0.0097) mutations were characteristic of ICC, while KRAS (p=0.0019) and TP53 (p=0.0019) were more frequent in ECC and GBC. Multivariate analysis identified tumour stage and TP53 mutations as independent predictors of survival. Alterations in chromatin remodeling genes (ARID1A, BAP1, PBRM1, SMARCB1) were seen in 31% of cases. Potentially actionable mutations were seen in 104/153 (68%) cancers: i) KRAS/NRAS/BRAF mutations were found in 34% of cancers; ii) mTOR pathway activation was documented by immunohistochemistry in 51% of cases and by mutations in mTOR pathway genes in 19% of cancers; iii) TGF-ß/Smad signaling was altered in 10.5% cancers; iv) mutations in tyrosine kinase receptors were found in 9% cases. Our study identified molecular subgroups of cholangiocarcinomas that can be explored for specific drug targeting in clinical trials.

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“…However, ERBB1 (EGFR) and ERBB2 (HER2/Neu) are the two RTKs most frequently dysregulated in the molecular pathogenesis of CCA [22,23]. In addition, this is an attractive pathway for therapeutic targeting since TKIs are effective antitumor agents in other cancers.…”

Section: Rationale For Targeting Candidate Oncogenic Signaling Pathwaysmentioning

confidence: 99%

“…In CCA, overexpression of EGFR and HER2 was reported in 10–32% and 20–30% of tumors, respectively [22,23]. BTC with increased EGFR and HER2 expression displayed copy number (CN) gains in 77 and 79% of cases, respectively [24].…”

Section: Rationale For Targeting Candidate Oncogenic Signaling Pathwaysmentioning

confidence: 99%

A perspective on molecular therapy in cholangiocarcinoma: present status and future directions

Andersen

Thorgeirsson

2013

Hepatic Oncol.

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SUMMARY Cholangiocarcinoma (CCA) is an orphan cancer with limited understanding of its genetic and genomic pathogenesis. Typically, it is highly treatment-refractory and patient outcome is dismal. Currently, there are no approved therapeutics for CCA and surgical resection remains the only option with curative intent. Clinical trials are currently being performed in a mixed cohort of biliary tract cancers that includes intrahepatic CCA, extrahepatic/perihilar CCA, distal extrahepatic CCA, gallbladder carcinoma and, in rare cases, even pancreatic cancers. Today, clinical trials fail primarily because they are underpowered mixed cohorts and designed without intent to enrich for markers to optimize success for targeted therapy. This review aims to emphasize current clinical attempts for targeted therapy of CCA, as well as highlight promising new candidate pathways revealed by translational genomics.

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Targeted therapy for biliary tract cancers

Cited by 26 publications

References 79 publications

Epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin A inhibits the growth of cholangiocarcinoma cells

Epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin A inhibits the growth of cholangiocarcinoma cells

Multigene mutational profiling of cholangiocarcinomas identifies actionable molecular subgroups

A perspective on molecular therapy in cholangiocarcinoma: present status and future directions

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