Exploring subclass-specific therapeutic agents for hepatocellular carcinoma by informatics-guided drug screen
Chen Yang1, Junfei Chen2,3, Yan Li4
1Department of Liver Surgery and Shanghai Cancer Institute, State Key Laboratory of Oncogenes and Related Genes, Renji Hospital, Shanghai Jiao Tong University School of Medicine, China.
Abstract:
Almost all currently approved systemic therapies for hepatocellular carcinoma (HCC) failed to achieve satisfactory therapeutic effect. Exploring tailored treatment strategies for different individuals provides an approach with the potential to maximize clinical benefit. Previously, multiple studies have reported that hepatoma cell lines belonging to different molecular subtypes respond differently to the same treatment. However, these studies only focused on a small number of typical chemotherapy or targeted drugs across limited cell lines due to time and cost constraints. To compensate for the deficiency of previous experimental researches as well as link molecular classification with therapeutic response, we conducted a comprehensive in silico screening, comprising nearly 2000 compounds, to identify compounds with subclass-specific efficacy. Here, we first identified two transcriptome-based HCC subclasses (AS1 and AS2) and then made comparison of drug response between two subclasses. As a result, we not only found that some agents previously considered to have low efficacy in HCC treatment might have promising therapeutic effects for certain subclass, but also identified novel therapeutic compounds that were not routinely used as anti-tumor drugs in clinic. Discovery of agents with subclass-specific efficacy has potential in changing the status quo of population-based therapies in HCC and providing new insights into precision oncology.
Insights
Hepatocellular carcinoma (HCC) treatments are often ineffective. This study identified two HCC subclasses and screened nearly 2000 compounds, discovering subclass-specific drugs for personalized cancer therapy and precision oncology.
Area of Science:
- Oncology
- Genomics
- Pharmacology
Background:
- Systemic therapies for hepatocellular carcinoma (HCC) demonstrate limited efficacy.
- Individualized treatment strategies hold potential for maximizing clinical benefit in HCC.
- Previous research on drug response across HCC molecular subtypes is constrained by limited drug and cell line scope.
Purpose of the Study:
- To conduct a comprehensive in silico screening of approximately 2000 compounds to identify agents with subclass-specific efficacy in HCC.
- To link molecular classification of HCC with therapeutic response.
- To discover novel therapeutic compounds and repurpose existing agents for specific HCC subclasses.
Main Methods:
- Identification of two transcriptome-based HCC subclasses (AS1 and AS2).
- In silico screening of nearly 2000 compounds for differential drug response between HCC subclasses.
- Comparative analysis of drug efficacy across identified HCC subclasses.
Main Results:
- Discovery of compounds with subclass-specific efficacy in hepatocellular carcinoma.
- Identification of potential therapeutic effects for certain agents in specific HCC subclasses, challenging previous assumptions of low efficacy.
- Uncovering novel therapeutic compounds not typically used in anti-tumor therapy.
Conclusions:
- Subclass-specific drug efficacy in HCC offers a promising avenue for precision oncology.
- The findings have the potential to shift the paradigm from population-based therapies to tailored treatment strategies for HCC.
- This research provides new insights into personalized cancer treatment by linking molecular subtypes with drug response.
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