Cholangiocarcinomas (CCAs) are the second-most common primary liver cancers. CCAs represent a group of highly heterogeneous tumors classified based on anatomical localization into intra- (iCCA) and extrahepatic CCA (eCCA). In contrast to eCCA, the incidence of iCCA is increasing worldwide. Curative treatment strategies for all CCAs involve oncological resection followed by adjuvant chemotherapy in early stages, whereas chemotherapy is administered at advanced stages of disease. Due to late diagnosis, high recurrence rates, and limited treatment options, the prognosis of patients remains poor. Comprehensive molecular characterization has further revealed considerable heterogeneity and distinct prognostic and therapeutic traits for iCCA and eCCA, indicating that specific treatment modalities are required for different subclasses. Several druggable alterations and oncogenic drivers such as fibroblast growth factor receptor 2 gene fusions and hotspot mutations in isocitrate dehydrogenase 1 and 2 mutations have been identified. Specific inhibitors have demonstrated striking antitumor activity in affected subgroups of patients in phase II and III clinical trials. Thus, improved understanding of the molecular complexity has paved the way for precision oncological approaches. Here, we outline current advances in targeted treatments and immunotherapeutic approaches. In addition, we delineate future perspectives for different molecular subclasses that will improve the clinical care of iCCA patients.

Liver metastases are the most common site of metastatic spread in colorectal cancer. Current treatment approaches involve effective systemic therapies in combination with surgical and/or interventional strategies. Multimodal strategies greatly improved clinical outcomes of patients with metastatic colorectal cancer over the last decades. Identification of predictive and prognostic biomarkers helped to comprehensively refine individual targeted treatment approaches and resulted in median overall survival rates of 30 months or longer. Current guidelines, thus, recommend treatment selection according to patients’ performance status, tumor localization and stage as well as the tumor’s molecular and genetic status. Here, we outline the latest developments in molecular decision-making for patients with upfront resectable, potentially or initially unresectable and non/never-resectable colorectal cancer liver metastases.

Development of primary liver cancer is a multistage process. Detailed understanding of sequential epigenetic alterations is largely missing. Here, we performed Infinium Human Methylation 450k BeadChips and RNA-Seq analyses for genome-wide methylome and transcriptome profiling of cirrhotic liver ( n = 7), low- ( n = 4) and high-grade ( n = 9) dysplastic lesions, and early ( n = 5) and progressed ( n = 3) hepatocellular carcinomas (HCC) synchronously detected in 8 patients with HCC with chronic hepatitis B infection. Integrative analyses of epigenetically driven molecular changes were identified and validated in 2 independent cohorts comprising 887 HCCs. Mitochondrial DNA sequencing was further employed for clonality analyses, indicating multiclonal origin in the majority of investigated HCCs. Alterations in DNA methylation progressively increased from liver cirrhosis (CL) to dysplastic lesions and reached a maximum in early HCCs. Associated early alterations identified by Ingenuity Pathway Analysis (IPA) involved apoptosis, immune regulation, and stemness pathways, while late changes centered on cell survival, proliferation, and invasion. We further validated 23 putative epidrivers with concomitant expression changes and associated with overall survival. Functionally, Striatin 4 (STRN4) was demonstrated to be epigenetically regulated, and inhibition of STRN4 significantly suppressed tumorigenicity of HCC cell lines. Overall, application of integrative genomic analyses defines epigenetic driver alterations and provides promising targets for potentially novel therapeutic approaches.

Introduction The hallmarks of many cancers, including hepatocellular carcinoma (HCC), are apoptosis resistance, poor response to the drug treatment or quick relapse after initial remission. Aim To dissect molecular drivers of drug resistance frequently observed in HCC, particularly in the patients who demonstrated the worst response to sorafenib. Methods Integrative RNA sequencing and whole-exome sequencing analyses were employed to identify predictive markers of sorafenib resistance based on our cohort of 19 HCC patients. Potential drivers of drug resistance were evaluated by IPA and GSEA. Validation was performed in our in vitro model of sorafenib resistance by western blot and in publicly available data sets (GEPIA), followed by siRNA or peptide (R18) inhibition of selected molecular target candidates. Results Patients with worst response (n=7) were characterized by significantly shorter treatment duration and poor overall survival than good responders (n=12) (66,6 months and 133,3 months, respectively; p < 0,0004). Molecular analyses revealed that the worst subgroup was associated with activation of ERK and hypoxia-related scaffold proteins from the 14-3-3 protein family. Further, in our focus group, analysis based on gene expression signature showed significant enrichment of gene sets associated with Hippo/YAP signaling, ERK signaling and hypoxia. From hypoxia-related targets, we could observe that 14-3-3 zeta and sigma proteins might play a significant role in the acquisition of drug resistance. Conclusion Defining the actionable targets of resistance and subsequent inhibition, e. g. 14-3-3 zeta and/or sigma protein might be of great help to delineate distinct molecular alterations driving sorafenib resistance. Publication Date: 26 January 2022 (online) © 2022. Thieme. All rights reserved. Georg Thieme Verlag Rüdigerstraße 14, 70469 Stuttgart, Germany