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Precision Medicine in Hepatobiliary Cancer: Preclinical and Clinical Evidence

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A special issue of Journal of Personalized Medicine (ISSN 2075-4426). This special issue belongs to the section "Mechanisms of Diseases".

Deadline for manuscript submissions: closed (5 April 2022) | Viewed by 9014

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Special Issue Editor

Prof. Dr. Diego F. Calvisi

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Guest Editor

Institute of Pathology, University of Regensburg, 93053 Regensburg, Germany
Interests: liver cancer; hepatocellular carcinoma; cholangiocarcinoma; hepatoblastoma; tumor metabolism; signal transduction; epigenetic and genetic alterations; precision medicine

Special Issue Information

Dear Colleagues,

Primary liver cancer (PLC) is a frequent and deadly tumor worldwide. PLC consists mainly of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) in the adult, whereas hepatoblastoma (HB) is the prevalent hepatic malignancy in childhood. These different tumor entities are commonly characterized by clinical aggressiveness and poor prognosis due to limited therapeutic options. In particular, advanced forms of HCC and CCA and subsets of HB remain almost incurable when detected at advanced stages.

In the last decade, as in many other tumor types, whole-genome sequencing studies together with a plethora of transcriptomic, proteomic, and metabolomic approaches have unraveled the molecular landscape of PLC. In addition, several in vitro and in vivo models have been generated to evaluate the possible vulnerability of tumors to innovative therapies. As a result, specific genetic and epigenetic events and peculiar metabolic features of the tumors have been identified. Effective and highly specific therapeutic approaches have been developed for some of them, and the concept of “precision medicine” (one patient = one treatment) has been established. However, the resulting benefits in patients’ overall survival have been limited to date, mainly due to the appearance of drug resistance. Furthermore, the complexity of pathways’ functional crosstalk and compensatory mechanisms have often hindered the potency and effectiveness of therapies in clinical trials.

Given the importance of hepatobiliary tumors in medicine and research, the Journal of Personalized Medicine is launching this Special Issue.

We warmly encourage you and your co-workers to submit your articles reporting on this topic. Reviews, original articles, or clinical cases dealing with innovative molecular therapeutics, with a particular focus on individualized approaches, as well as articles providing an up-to-date overview of the use of biomarkers in therapy management, are welcome.

Prof. Dr. Diego F. Calvisi
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.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Personalized Medicine is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 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.

Keywords

hepatobiliary tumors
precision medicine
targeted therapies
tumor markers
experimental therapeutics
drug testing

Published Papers (4 papers)

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Research

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23 pages, 4051 KiB

Open AccessArticle

Wnt/β-Catenin-Pathway Alterations and Homologous Recombination Deficiency in Cholangiocarcinoma Cell Lines and Clinical Samples: Towards Specific Vulnerabilities

by Alexander Scheiter, Frederik Hierl, Ingrid Winkel, Felix Keil, Margit Klier-Richter, Cédric Coulouarn, Florian Lüke, Arne Kandulski, Matthias Evert, Wolfgang Dietmaier, Diego F. Calvisi and Kirsten Utpatel

J. Pers. Med. 2022, 12(8), 1270; https://doi.org/10.3390/jpm12081270 - 01 Aug 2022

Cited by 2 | Viewed by 2130

Abstract

Cholangiocarcinoma (CCA) features a dismal prognosis with limited treatment options. Genomic studies have unveiled several promising targets in this disease, including fibroblast growth factor receptor (FGFR) fusions and isocitrate dehydrogenase (IDH) mutations. To fully harness the potential of genomically informed therapies in CCA, it is necessary to thoroughly characterize the available model organisms, including cell lines. One parameter to investigate in CCA is homologous recombination deficiency (HRD). While mutations in homologous recombinational repair (HRR)-related genes have been detected, their predictive value remains undetermined. Using a targeted next-generation sequencing approach, we analyzed 12 human CCA cell lines and compared them to 62 CCA samples of the molecular tumor board cohort. The AmoyDx^® HRD Focus Panel was employed to determine corresponding genomic scar scores (GSS). Ten of twelve cell lines harbored alterations in common HRR-related genes, and five cell lines were HRD-positive, although this parameter did not correlate well with Olaparib sensitivity. Moreover, functionally relevant APC and β-catenin mutations were registered, which were also detected in 4/176 (2.3%) samples on a CCA microarray. Although rare, these alterations were exclusive to large duct type CCA with associated intraductal papillary neoplasms of the bile duct (IPNB) in 3 cases, pointing at a distinct form of cholangiocarcinogenesis with potential specific vulnerabilities. Full article

(This article belongs to the Special Issue Precision Medicine in Hepatobiliary Cancer: Preclinical and Clinical Evidence)

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20 pages, 6424 KiB

Open AccessArticle

Novel Thienyl-Based Tyrosine Kinase Inhibitors for the Treatment of Hepatocellular Carcinoma

by Andi Ma, Bernhard Biersack, Nils Goehringer, Bianca Nitzsche and Michael Höpfner

J. Pers. Med. 2022, 12(5), 738; https://doi.org/10.3390/jpm12050738 - 01 May 2022

Cited by 2 | Viewed by 1821

Abstract

New medical treatments are urgently needed for advanced hepatocellular carcinoma (HCC). Recently, we showed the anticancer effects of novel thiophene-based kinase inhibitors. In this study, we further characterized the antineoplastic effects and modes of action of the two most promising inhibitors, Thio-Iva and Thio-Dam, and compared their effects with the clinically relevant multi-kinase inhibitor, sorafenib, in HCC cells. Crystal violet staining and real-time cell growth monitoring showed pronounced antiproliferative effects in Huh-7 and SNU-449 cells with IC₅₀ values in the (sub-)micromolar range. Long-term incubation experiments revealed the reduced clonogenicity of Thio-Iva and Thio-Dam-treated HCC cells. LDH-release tests excluded cytotoxicity as an unspecific mode of action of the inhibitors, while flow cytometry analysis revealed a dose-dependent and pronounced G2/M phase cell cycle arrest and cyclin B1 suppression. Additionally, mitochondria-driven apoptosis was observed through the cytosolic increase of reactive oxygen species, a concomitant PARP cleavage, and caspase-3 induction. Both compounds were found to effectively inhibit the capillary tube formation of endothelial EA.hy926 cells in vitro, pointing towards additional antiangiogenic effects. Antiangiogenic and antineoplastic effects were confirmed in vivo by CAM assays. In summary, the thienyl-acrylonitrile derivatives, Thio-Iva and Thio-Dam, exert significant antineoplastic and antiangiogenic effects in HCC cells. Full article

(This article belongs to the Special Issue Precision Medicine in Hepatobiliary Cancer: Preclinical and Clinical Evidence)

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13 pages, 1284 KiB

Open AccessFeature PaperArticle

Benchmarking Outcomes after Ablative Radiotherapy for Molecularly Characterized Intrahepatic Cholangiocarcinoma

by Brian De, Ibrahim Abu-Gheida, Aashini Patel, Sylvia S. W. Ng, Mohamed Zaid, Connor P. Thunshelle, Dalia Elganainy, Kelsey L. Corrigan, Michael K. Rooney, Milind Javle, Kanwal Raghav, Sunyoung S. Lee, Jean-Nicolas Vauthey, Ching-Wei D. Tzeng, Hop S. Tran Cao, Ethan B. Ludmir, Bruce D. Minsky, Grace L. Smith, Emma B. Holliday, Cullen M. Taniguchi, Albert C. Koong, Prajnan Das and Eugene J. Koay Show full author list Hide full author list

J. Pers. Med. 2021, 11(12), 1270; https://doi.org/10.3390/jpm11121270 - 01 Dec 2021

Cited by 5 | Viewed by 2332

Abstract

We have previously shown that ablative radiotherapy (A-RT) with a biologically effective dose (BED₁₀) ≥ 80.5 Gy for patients with unresectable intrahepatic cholangiocarcinoma (ICC) is associated with longer survival. Despite recent large-scale sequencing efforts in ICC, outcomes following RT based on genetic alterations have not been described. We reviewed records of 156 consecutive patients treated with A-RT for unresectable ICC from 2008 to 2020. For 114 patients (73%), next-generation sequencing provided molecular profiles. The overall survival (OS), local control (LC), and distant metastasis-free survival (DMFS) were estimated using the Kaplan–Meier method. Univariate and multivariable Cox analyses were used to determine the associations with the outcomes. The median tumor size was 7.3 (range: 2.2–18.2) cm. The portal vein thrombus (PVT) was present in 10%. The RT median BED₁₀ was 98 Gy (range: 81–144 Gy). The median (95% confidence interval) follow-up was 58 (42–104) months from diagnosis and 39 (33–74) months from RT. The median OS was 32 (29–35) months after diagnosis and 20 (16–24) months after RT. The one-year OS, LC, and intrahepatic DMFS were 73% (65–80%), 81% (73–87%), and 34% (26–42%). The most common mutations were in IDH1 (25%), TP53 (22%), ARID1A (19%), and FGFR2 (13%). Upon multivariable analysis, the factors associated with death included worse performance status, larger tumor, metastatic disease, higher CA 19-9, PVT, satellitosis, and IDH1 and PIK3CA mutations. TP53 mutation was associated with local failure. Further investigation into the prognostic value of individual mutations and combinations thereof is warranted. Full article

(This article belongs to the Special Issue Precision Medicine in Hepatobiliary Cancer: Preclinical and Clinical Evidence)

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Review

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16 pages, 1325 KiB

Open AccessReview

Translational Value of Tumor-Associated Lymphangiogenesis in Cholangiocarcinoma

by Massimiliano Cadamuro, Adriana Romanzi, Maria Guido, Samantha Sarcognato, Umberto Cillo, Enrico Gringeri, Giacomo Zanus, Mario Strazzabosco, Paolo Simioni, Erica Villa and Luca Fabris

J. Pers. Med. 2022, 12(7), 1086; https://doi.org/10.3390/jpm12071086 - 30 Jun 2022

Cited by 6 | Viewed by 2175

Abstract

The prognosis of cholangiocarcinoma remains poor in spite of the advances in immunotherapy and molecular profiling, which has led to the identification of several targetable genetic alterations. Surgical procedures, including both liver resection and liver transplantation, still represent the treatment with the best curative potential, though the outcomes are significantly compromised by the early development of lymph node metastases. Progression of lymphatic metastasis from the primary tumor to tumor-draining lymph nodes is mediated by tumor-associated lymphangiogenesis, a topic largely overlooked until recently. Recent findings highlight tumor-associated lymphangiogenesis as paradigmatic of the role played by the tumor microenvironment in sustaining cholangiocarcinoma invasiveness and progression. This study reviews the current knowledge about the intercellular signaling and molecular mechanism of tumor-associated lymphangiogenesis in cholangiocarcinoma in the hope of identifying novel therapeutic targets to halt a process that often limits the success of the few available treatments. Full article

(This article belongs to the Special Issue Precision Medicine in Hepatobiliary Cancer: Preclinical and Clinical Evidence)

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