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Molecular targeted drugs, comprehensive classification and preclinical models for the implementation of precision immune oncology in hepatocellular carcinoma

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Abstract

Hepatocellular carcinoma (HCC) is a complex heterogeneous disease with high morbidity and mortality. Recent progress in molecular targeted drugs including multikinase inhibitors and immune checkpoint inhibitors has demonstrated substantial survival improvement in patients with advanced HCC, but it remains as a challenging issue to discover surrogate markers for precisely distinguishing responders and non-responders. Genome-based medicine has changed cancer treatment from empirical use of cytotoxic agents to theoretical use of molecular targeted drugs in various types of cancer, while not in HCC due to lack of druggable targets. Integrated genomic and transcriptomic analysis reveal that HCC is divided into three major subtypes, proliferative, CTNNB1-mutated and metabolic disease-associated, with distinctive molecular and immunological features, and an increasing number of studies provide evidence for the close correlation between the subtype and the response to molecular targeted drugs using both of clinical data and preclinical models. Dozens of immunocompetent mouse models, such as hydrodynamic tail vain injection models and implantable syngeneic models, reflect molecular characteristics and tumor immune microenvironment of the subtypes, and help us to evaluate the efficacy of single and combination therapies and understand the molecular mechanisms underlying vulnerability and resistance to them. Thus, the consensus classification and relevant preclinical models could accelerate the establishment of predictive biomarkers and the development of subtype-specific therapies.

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Funding

This work was supported by Grants-in-Aid for Scientific Research (A; 19H01055) and Challenging Research (Exploratory; 20K21627) from the Ministry of Education, Culture, Sports, Science and Technology of Japan; Research Grant from the Princess Takamatsu Cancer Research Fund; P-CREATE (JP19cm0106540), and Program for Basic and Clinical Research on Hepatitis (JP21fk0210090, JP20fk0210060) from AMED (Japan Agency for Medical Research and Development).

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  1. Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan

    Shu Shimada & Shinji Tanaka

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  1. Shu Shimada
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Correspondence to Shinji Tanaka.

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Shimada, S., Tanaka, S. Molecular targeted drugs, comprehensive classification and preclinical models for the implementation of precision immune oncology in hepatocellular carcinoma. Int J Clin Oncol 27, 1101–1109 (2022). https://doi.org/10.1007/s10147-022-02174-0

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  • DOI: https://doi.org/10.1007/s10147-022-02174-0

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