Improvement in the Current Therapies for Hepatocellular Carcinoma Using a Systems Medicine Approach

Abstract

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer‐related death primarily due to the lack of effective targeted therapies. Despite the distinct morphological and phenotypic patterns of HCC, treatment strategies are restricted to relatively homogeneous therapies, including multitargeted tyrosine kinase inhibitors and immune checkpoint inhibitors. Therefore, more effective therapy options are needed to target dysregulated metabolic and molecular pathways in HCC. Integrative genomic profiling of HCC patients provides insight into the most frequently mutated genes and molecular targets, including telomerase reverse transcriptase, the TP53 gene, and the Wnt/β‐catenin signaling pathway oncogene (CTNNB1). Moreover, emerging techniques, such as genome‐scale metabolic models may elucidate the underlying cancer‐specific metabolism, which allows for the discovery of potential drug targets and identification of biomarkers. De novo lipogenesis has been revealed as consistently upregulated since it is required for cell proliferation in all HCC patients. The metabolic network‐driven stratification of HCC patients in terms of redox responses, utilization of metabolites, and subtype‐specific pathways may have clinical implications to drive the development of personalized medicine. In this review, the current and emerging therapeutic targets in light of molecular approaches and metabolic network‐based strategies are summarized, prompting effective treatment of HCC patients.

Current status of ctDNA in precision oncology for hepatocellular carcinoma

“…The expression of those genes can function as a compound tumor promoter involved in the progression of HCC based on an analysis of HCC tissue samples, which is consistent with the findings of a targeted sequence analysis of ctDNA [87,88]. The recently reported small molecule blockade that aimed at attacking WNT ligands or receptors, such as LGK874 and OMP-54F28, preventing β-catenin degradation, such as NSAIDs, or inhibiting β-catenin from interacting with nuclear transcription, such as vitamin D and CWP232291, to block the WNT signaling pathway, are still in phase I or II clinical trials [67][68][69].…”

Scirrhous Hepatocellular Carcinoma: Systematic Review and Pooled Data Analysis of Clinical, Radiological, and Histopathological Features

“… 50 System-based approach and genomic profiling have identified numerous potential targets in HCC treatment, such as Wnt/β-catenin pathway, telomerases, and p53. 51 However, an individualized therapy strategy is far from implementation for HCC patients. Additionally, no profiling has thus far been made of atypical HCCs, an approach with the potential to identify targets with adequate subtype and patient specificity.…”

Stratification of patients with clear cell renal cell carcinoma to facilitate drug repositioning

“…Systems biology-based methods are widely employed to identify drug targets and predict therapeutic agents based on drug repositioning ( Altay et al., 2020 ; Lam et al., 2020 , 2021 ; Mardinoglu et al., 2018 ; Ozcan et al., 2020 ). Genome-scale metabolic models (GEMs), one of the commonly used systems biology tools, have been used as a powerful tool to identify the potential drug targets inducing inhibition of tumor cell proliferation, which could be applied in drug repositioning ( Mardinoglu and Nielsen, 2012 ; Zhang and Hua, 2015 ).…”