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Cutting Edge Research for Exploration of Biomolecules for Gemcitabine-Based Chemo-Resistant Advanced Bile Duct Cancer: from Basic Study to Clinical Trial

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A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: closed (31 May 2021) | Viewed by 17406

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Special Issue Editor

Prof. Dr. Chun-Nan Yeh

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Guest Editor

Chang Gung Memorial Hospital, Taipei, Taiwan
Interests: hepatobiliary and pancreatic surgery; minimal invasive GI surgery; gastrointestinal stromal tumor; translational research of HBP cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cholangiocarcinoma (CCA) has been identified as a highly malignant cancer arising from epithelial cells of the bile duct, including intrahepatic, perihilar, and extrahepatic. Even with high-resolution imaging tools for diagnosis (abdominal ultrasound, computed tomography (CT) and magnetic resonance cholangio-pancreaticography (MRCP)), CCAs are usually diagnosed at an advanced stage with poor prognosis or high recurrence rate after primary operation.

CCA has over the last 10–20 years become the focus of increasing concern, largely due to its rising incidence and high mortality rates worldwide, even in Taiwan. The significant increases in mortality rates from this primary hepatobiliary cancer have coincided with a rapidly growing interest among clinicians, investigators, and patient advocates seeking greater mechanistic insights and more effective biomarker-driven targeted approaches for managing and/or preventing this challenging liver cancer.

However, gemcitabine and cisplatin has been the standard treatment in first-line chemotherapy since 2010. Clinical trials have evaluated molecular targeted therapies in combination with chemotherapy, but none of the completed phase III trials and phase II studies have demonstrated a positive result of improvement in progression-free survival (PFS) and overall survival (OS) in patients with advanced CCA.

In order to serve as a reference for further research and treatment strategies to overcome gemcitabine-resistance CCAs, this Special Issue entitled “Cutting-Edge Research for Exploration of Biomolecules for Gemcitabine-Based Chemoresistant Advanced Bile Duct Cancers: From Basic Study to Clinical Trial” aims to integrate the cutting-edge research and expand knowledge on a wide range of topics, including p53, micro-RNA, bioinformatics, clinical trials, and other related topics.

Prof. Chun-Nan Yeh
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (6 papers)

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Editorial

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2 pages, 162 KiB

Open AccessEditorial

Cutting Edge Research for Exploration of Biomolecules for Gemcitabine-Based Chemo-Resistant Advanced Bile Duct Cancer: From Basic Study to Clinical Trial

by Chiao-En Wu and Chun-Nan Yeh

Biomolecules 2021, 11(11), 1626; https://doi.org/10.3390/biom11111626 - 03 Nov 2021

Cited by 4 | Viewed by 1386

Abstract

Bile duct cancer (BDC) has been identified as a highly aggressive cancer arising from epithelial cells of the bile duct, including intrahepatic, perihilar, and extrahepatic [...] Full article

(This article belongs to the Special Issue Cutting Edge Research for Exploration of Biomolecules for Gemcitabine-Based Chemo-Resistant Advanced Bile Duct Cancer: from Basic Study to Clinical Trial)

Research

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17 pages, 3968 KiB

Open AccessArticle

ATM Inhibitor Suppresses Gemcitabine-Resistant BTC Growth in a Polymerase θ Deficiency-Dependent Manner

by Yi-Ru Pan, Chiao-En Wu and Chun-Nan Yeh

Biomolecules 2020, 10(11), 1529; https://doi.org/10.3390/biom10111529 - 09 Nov 2020

Cited by 9 | Viewed by 2644

Abstract

Patients with advanced biliary tract cancer (BTC) inevitably experience progression after first-line, gemcitabine-based chemotherapy, due to chemo-resistance. The genetic alterations of DNA damage repair (DDR) genes are usually determined in BTC tumors. In this study, we found that the POLQ mRNA levels are downregulated and the ataxia-telangiectasia mutated (ATM) inhibitor AZD0156 was more sensitive in gemcitabine-resistant BTC sublines than in the parental cell lines. The knockdown of DNA polymerase θ does not affect cell proliferation, but its combination with the ATM inhibitor facilitated cell death in gemcitabine-resistant and gemcitabine-intensive BTC cells. Moreover, in the DNA damage caused by photon, hydrogen peroxide, or chemotherapy drugs, synthetic lethal interactions were found in combination with ATM inhibition by AZD0156 and DNA polymerase θ depletion, resulting in increased DNA damage accumulation and micronucleus formation, as well as reduced cell survival and colony formation. Collectively, our results reveal that ATM acts as a potential target in gemcitabine-resistant and DNA polymerase θ-deficient BTC. Full article

(This article belongs to the Special Issue Cutting Edge Research for Exploration of Biomolecules for Gemcitabine-Based Chemo-Resistant Advanced Bile Duct Cancer: from Basic Study to Clinical Trial)

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Review

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20 pages, 719 KiB

Open AccessReview

Development of Possible Next Line of Systemic Therapies for Gemcitabine-Resistant Biliary Tract Cancers: A Perspective from Clinical Trials

by Nai-Jung Chiang, Li-Tzong Chen, Yan-Shen Shan, Chun-Nan Yeh and Ming-Huang Chen

Biomolecules 2021, 11(1), 97; https://doi.org/10.3390/biom11010097 - 13 Jan 2021

Cited by 7 | Viewed by 3151

Abstract

Biliary tract cancer (BTC) compromises a heterogenous group of tumors with poor prognoses. Curative surgery remains the first choice for localized disease; however, most BTC patients have had unresectable or metastatic disease. The gold standard therapy for these patients is chemotherapy with gemcitabine and cisplatin. There are no consensus guidelines for standard treatment in a second-line setting, although the data of the ABC-06 trial showed a slight survival benefit from oxaliplatin and 5-fluorouracil combination chemotherapy. Recent progress in comprehensive genomic profiling for advanced BTC (ABTC) has helped to clarify tumorigenesis and facilitate the coming era of precision medicine. Generally, targeted agents fail to show significant clinical benefits in unselected populations. Only fibroblast growth factor receptor 2 (FGFR2) fusion and isocitrate dehydrogenase (IDH)- and BRAF mutation-enriched populations have survival benefits from the corresponding inhibitors. Several interesting targeted agents for monotherapies or combination therapies with other compounds are currently ongoing or recruiting. Here, we review the published data from clinical trials of second-line therapies after the failure of gemcitabine-based chemotherapy in ABTC. The results were stratified by different genetic alternations, as well as by chemotherapy, targeted therapy and immunotherapy. Full article

(This article belongs to the Special Issue Cutting Edge Research for Exploration of Biomolecules for Gemcitabine-Based Chemo-Resistant Advanced Bile Duct Cancer: from Basic Study to Clinical Trial)

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17 pages, 2302 KiB

Open AccessReview

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

by Chiao-En Wu, Yi-Ru Pan, Chun-Nan Yeh and John Lunec

Biomolecules 2020, 10(11), 1474; https://doi.org/10.3390/biom10111474 - 23 Oct 2020

Cited by 21 | Viewed by 3729

Abstract

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. Full article

(This article belongs to the Special Issue Cutting Edge Research for Exploration of Biomolecules for Gemcitabine-Based Chemo-Resistant Advanced Bile Duct Cancer: from Basic Study to Clinical Trial)

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22 pages, 1900 KiB

Open AccessReview

The Emerging Role of MicroRNAs in Regulating the Drug Response of Cholangiocarcinoma

by Wen-Kuan Huang and Chun-Nan Yeh

Biomolecules 2020, 10(10), 1396; https://doi.org/10.3390/biom10101396 - 30 Sep 2020

Cited by 9 | Viewed by 2354

Abstract

Cholangiocarcinoma (CCA) is the most common biliary malignancy, and has a poor prognosis. The median overall survival with the standard-of-care chemotherapy (Gemcitabine and cisplatin) in patients with advanced-stage CCA is less than one year. The limited efficacy of chemotherapy or targeted therapy remains a major obstacle to improving survival. The mechanisms involved in drug resistance are complex. Research efforts focusing on the distinct molecular mechanisms underlying drug resistance should prompt the development of treatment strategies that overcome chemoresistance or targeted drug resistance. MicroRNAs (miRNAs) are a class of evolutionarily conserved, short noncoding RNAs regulating gene expression at the post-transcriptional level. Dysregulated miRNAs have been shown to participate in almost all CCA hallmarks, including cell proliferation, migration and invasion, apoptosis, and the epithelial-to-mesenchymal transition. Emerging evidence demonstrates that miRNAs play a role in regulating responses to chemotherapy and targeted therapy. Herein, we present an overview of the current knowledge on the miRNA-mediated regulatory mechanisms underlying drug resistance among CCA. We also discuss the application of miRNA-based therapeutics to CCA, providing the basis for innovative treatment approaches. Full article

(This article belongs to the Special Issue Cutting Edge Research for Exploration of Biomolecules for Gemcitabine-Based Chemo-Resistant Advanced Bile Duct Cancer: from Basic Study to Clinical Trial)

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25 pages, 27899 KiB

Open AccessReview

Omics-Based Platforms: Current Status and Potential Use for Cholangiocarcinoma

by Yu-Chan Chang, Ming-Huang Chen, Chun-Nan Yeh and Michael Hsiao

Biomolecules 2020, 10(10), 1377; https://doi.org/10.3390/biom10101377 - 28 Sep 2020

Cited by 4 | Viewed by 3575

Abstract

Cholangiocarcinoma (CCA) has been identified as a highly malignant cancer that can be transformed from epithelial cells of the bile duct, including intrahepatic, perihilar and extrahepatic. High-resolution imaging tools (abdominal ultrasound, computed tomography and percutaneous transhepatic cholangial drainage) are recruited for diagnosis. However, the lack of early diagnostic biomarkers and treatment evaluation can lead to serious outcomes and poor prognosis (i.e., CA19-9, MUC5AC). In recent years, scientists have established a large number of omics profiles to reveal underlying mechanisms and networks (i.e., IL-6/STAT3, NOTCH). With these results, we achieved several genomic alteration events (i.e., TP53_mut, KRAS_mut) and epigenetic modifications (i.e., DNA methylation, histone modification) in CCA cells and clinical patients. Moreover, we reviewed candidate gene (such as NF-kB, YAP1) that drive gene transcription factors and canonical pathways through transcriptomics profiles (including microarrays and next-generation sequencing). In addition, the proteomics database also indicates which molecules and their directly binding status could trigger dysfunction signatures in tumorigenesis (carbohydrate antigen 19-9, mucins). Most importantly, we collected metabolomics datasets and pivotal metabolites. These results reflect the pharmacotherapeutic options and evaluate pharmacokinetic/pharmacodynamics in vitro and in vivo. We reversed the panels and selected many potentially small compounds from the connectivity map and L1000CDS² system. In this paper, we summarize the prognostic value of each candidate gene and correlate this information with clinical events in CCA. This review can serve as a reference for further research to clearly investigate the complex characteristics of CCA, which may lead to better prognosis, drug repurposing and treatment strategies. Full article

(This article belongs to the Special Issue Cutting Edge Research for Exploration of Biomolecules for Gemcitabine-Based Chemo-Resistant Advanced Bile Duct Cancer: from Basic Study to Clinical Trial)

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