Targeted therapy in biliary tract cancers—current limitations and potentials in the future

Sahu, Selley; Sun, Weijing

doi:10.21037/jgo.2016.09.16

Cited by 33 publications

(20 citation statements)

References 79 publications

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“…Gemcitabine and cisplatin have been the standard treatments in first-line chemotherapy since the ABC-02 trial was published in 2010 [7]. Clinical trials have evaluated molecular targeted therapies in combination with chemotherapy; however, none of the completed phase III trials [8][9][10][11] and phase II studies [12][13][14][15] have demonstrated significant improvement in progression-free survival (PFS) and overall survival (OS) in patients with advanced BTCs [16]. Real word experience has confirmed the feasibility and safety of gemcitabine and cisplatin in advanced BTCs [6,17].…”

Section: Current Treatment For Biliary Tract Cancers (Btcs): Chemothementioning

confidence: 99%

Targeting P53 as a Future Strategy to Overcome Gemcitabine Resistance in Biliary Tract Cancers

Pan

Yeh

et al. 2020

Biomolecules

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Gemcitabine-based chemotherapy is the current standard treatment for biliary tract cancers (BTCs) and resistance to gemcitabine remains the clinical challenge. TP53 mutation has been shown to be associated with poor clinicopathologic characteristics and survival in patients with BTCs, indicating that p53 plays an important role in the treatment of these cancers. Herein, we comprehensively reviewed previous BTC preclinical research and early clinical trials in terms of p53, as well as novel p53-targeted treatment, alone or in combination with either chemotherapy or other targeted therapies in BTCs. Preclinical studies have demonstrated that p53 mutations in BTCs are associated with enhanced gemcitabine resistance, therefore targeting p53 may be a novel therapeutic strategy for treatment of BTCs. Directly targeting mutant p53 by p53 activators, or indirectly by targeting cell cycle checkpoint proteins (Chk1, ataxia telangiectasia related (ATR), and Wee1) leading to synthetic lethality, may be potential future strategies for gemcitabine-resistant p53 mutated BTCs. In contrast, for wild-type p53 BTCs, activation of p53 by inhibition of its negative regulators (MDM2 and wild-type p53-induced phosphatase 1 (WIP1)) may be alternative options. Combination therapies consisting of standard cytotoxic drugs and novel small molecules targeting p53 and related signaling pathways may be the future key standard approach to beat cancer.

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Section: Current Treatment For Biliary Tract Cancers (Btcs): Chemothementioning

confidence: 99%

Targeting P53 as a Future Strategy to Overcome Gemcitabine Resistance in Biliary Tract Cancers

Pan

Yeh

et al. 2020

Biomolecules

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“…Recent research has focused on target identification and selective inhibitors of several molecular signaling pathways ( 7 ). In earlier reports, genetic alterations were identified to be involved in CCA carcinogenesis, including point mutations in p53, B-Raf proto-oncogene serine/threonine kinase and V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog ( 8 , 9 ).…”

Section: Introductionmentioning

confidence: 99%

Potential candidate treatment agents for targeting of cholangiocarcinoma identified by gene expression profile analysis

et al. 2018

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Cholangiocarcinoma (CCA) remains to be a major health problem in several Asian countries including Thailand. The molecular mechanism of CCA is poorly understood. Early diagnosis is difficult, and at present, no effective therapeutic drug is available. The present study aimed to identify the molecular mechanism of CCA by gene expression profile analysis and to search for current approved drugs which may interact with the upregulated genes in CCA. Gene Expression Omnibus (GEO) was used to analyze the gene expression profiles of CCA patients and normal subjects. Using the Kyoto Encyclopedia of Genes and Genomes (KEGG), gene ontology enrichment analysis was also performed, with the KEGG pathway analysis indicating that pancreatic secretion, protein digestion and absorption, fat digestion and absorption, and glycerolipid metabolism may serve important roles in CCA oncogenesis. The drug signature database (DsigDB) was used to search for US Food and Drug Administration (FDA)-approved drugs potentially capable of reversing the effects of the upregulated gene expression in CCA. A total of 61 antineoplastic and 86 non-antineoplastic drugs were identified. Checkpoint kinase 1 was the most interacting with drug signatures. Many of the targeted protein inhibitors that were identified have been approved by the US-FDA as therapeutic agents for non-antineoplastic diseases, including cimetidine, valproic acid and lovastatin. The current study demonstrated an application for bioinformatics analysis in assessing the potential efficacy of currently approved drugs for novel use. The present results suggest novel indications regarding existing drugs useful for CCA treatment. However, further in vitro and in vivo studies are required to support the current predictions.

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“…This reflects the aggressiveness of this cancer and that while negative resection margins predict longer survival, they do not ensure cure. Additional or adjunctive new treatments may be needed preoperatively or postoperatively to improve the surgical outcome …”

Section: Discussionmentioning

confidence: 99%

Ultrasound surveillance for cholangiocarcinoma in an endemic area: A prove of survival benefits

Siripongsakun

Vidhyarkorn

Charuswattanakul

et al. 2018

J of Gastro and Hepatol

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Targeted therapy in biliary tract cancers—current limitations and potentials in the future

Cited by 33 publications

References 79 publications

Targeting P53 as a Future Strategy to Overcome Gemcitabine Resistance in Biliary Tract Cancers

Targeting P53 as a Future Strategy to Overcome Gemcitabine Resistance in Biliary Tract Cancers

Potential candidate treatment agents for targeting of cholangiocarcinoma identified by gene expression profile analysis

Ultrasound surveillance for cholangiocarcinoma in an endemic area: A prove of survival benefits

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