mTOR Inhibitors in Advanced Biliary Tract Cancers

Wu, Chiao‐En; Chen, Ming-Huang; Yeh, Chun‐Nan

doi:10.3390/ijms20030500

Cited by 28 publications

(20 citation statements)

References 116 publications

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“…Although its incidence is lower than that of hepatocellular carcinoma (HCC), its prognosis is much worse. CCA is a devastating cancer showing resistance to most known chemotherapeutic drugs; systemic chemotherapy is however the standard treatment (Banales et al, 2016; Chao-En et al., 2019). Hence, developing natural compounds as novel chemo-preventative agents has become a very promising option in the study of CCA treatment and therapy.…”

Section: Discussionmentioning

confidence: 99%

Pterostilbene, An Active Constituent of Blueberries, Suppresses Proliferation Potential of Human Cholangiocarcinoma via Enhancing the Autophagic Flux

et al. 2019

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Background: Human cholangiocarcinoma (CCA) is a highly lethal cancer that occurs in the biliary tract. It is characterized by early invasion, poor outcomes, and resistance to current chemotherapies. To date, an effective therapeutic strategy for this devastating and deadly disease is lacking. Pterostilbene, a natural compound found in the extracts of many plants including blueberries, kino tree, or dragon blood tree, has several health benefits. However, its effects on CCA have not been clarified. Here, we investigated the potential application of pterostilbene for the treatment of human CCA in vitro and in vivo. Methods: The effects of pterostilbene on CCA cells were determined by assessing cell viability (CCK), cell proliferation, and colony formation. Cell cycle arrest and apoptosis were measured by flow cytometric analysis, whereas proteins related to autophagy were detected by immunofluorescence and immunoblotting assays. A well-established xenograft mouse model was used to evaluate the effects of pterostilbene on tumor growth in vivo. Results: Pterostilbene induced dose-dependent and time-dependent cytotoxic effects, inhibited proliferation and colony formation, and caused S phase cell cycle arrest in CCA cells. Instead of triggering apoptotic cell death in these cells, pterostilbene was found to exert potent autophagy-inducing effects, and this correlated with p62 downregulation, elevated expression of endogenous Beclin-1, ATG5, and LC3-II, and increases in LC3 puncta. Pretreating cancer cells with the autophagy inhibitor 3-MA suppressed the induction of autophagy and antitumor activity caused by pterostilbene. Finally, we confirmed that pterostilbene inhibited tumor growth in a CCA xenograft mouse model with minimal general toxicity. Conclusion: Taken together, our findings indicate that pterostilbene, through the induction of autophagic flux, acts as an anti-cancer agent against CCA cells.

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Section: Discussionmentioning

confidence: 99%

Pterostilbene, An Active Constituent of Blueberries, Suppresses Proliferation Potential of Human Cholangiocarcinoma via Enhancing the Autophagic Flux

et al. 2019

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“…Biliary tract cancers (BTCs) including intrahepatic cholangiocarcinoma (iCCA), extrahepatic cholangiocarcinoma (eCCA), gallbladder cancer, and ampullary cancer are a group of relatively rare cancers arising from the epithelium of the biliary tract [1][2][3][4] and have aggressive biological behavior, as they are diagnosed at an advanced stage with poor prognosis and have a high recurrence rate after primary surgery [5,6]. Gemcitabine and cisplatin have been the standard treatments in first-line chemotherapy since the ABC-02 trial was published in 2010 [7].…”

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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“…The PI3K/AKT/mTOR pathway regulates cellular proliferation and angiogenesis through its interactions with the RAS/RAF/MEK pathway and the mTOR signaling pathway [78] (Figure 1). Mutations in PIK3CA, resulting in upregulation of the PI3K/AKT/mTOR pathway, have been identified in many cancer types, including in BTC [79].…”

Section: Pi3k/akt/mtor Pathwaymentioning

confidence: 99%

Targeted Therapies in Advanced Biliary Tract Cancer: An Evolving Paradigm

Chakrabarti

Kamgar

Mahipal

2020

Cancers

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Biliary tract cancers (BTCs) are a heterogeneous group of adenocarcinomas that originate from the epithelial lining of the biliary tree. BTCs are characterized by presentation with advanced disease precluding curative surgery, rising global incidence, and a poor prognosis. Chemotherapy is the mainstay of the current treatment, which results in a median overall survival of less than one year, underscoring the need for novel therapeutic agents and strategies. Next-generation sequencing-based molecular profiling has shed light on the underpinnings of the complex pathophysiology of BTC and has uncovered numerous actionable targets, leading to the discovery of new therapies tailored to the molecular targets. Therapies targeting fibroblast growth factor receptor (FGFR) fusion, isocitrate dehydrogenase (IDH) mutations, the human epidermal growth factor receptor (HER) family, DNA damage repair (DDR) pathways, and BRAF mutations have produced early encouraging results in selected patients. Current clinical trials evaluating targeted therapies, as monotherapies and in combination with other agents, are paving the way for novel treatment options. Genomic profiling of cell-free circulating tumor DNA that can assist in the identification of an actionable target is another exciting area of development. In this review, we provide a contemporaneous appraisal of the evolving targeted therapies and the ongoing clinical trials that will likely transform the therapeutic paradigm of BTC.

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mTOR Inhibitors in Advanced Biliary Tract Cancers

Cited by 28 publications

References 116 publications

Pterostilbene, An Active Constituent of Blueberries, Suppresses Proliferation Potential of Human Cholangiocarcinoma via Enhancing the Autophagic Flux

Pterostilbene, An Active Constituent of Blueberries, Suppresses Proliferation Potential of Human Cholangiocarcinoma via Enhancing the Autophagic Flux

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

Targeted Therapies in Advanced Biliary Tract Cancer: An Evolving Paradigm

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