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BMC Medical Informatics and Decision Making
Published in: BMC Medical Informatics and Decision Making 3/2020

Open Access 01-07-2020 | Research

Hybrid phenotype mining method for investigating off-target protein and underlying side effects of anti-tumor immunotherapy

Authors: Yuyu Zheng, Xiangyu Meng, Pierre Zweigenbaum, Lingling Chen, Jingbo Xia

Published in: BMC Medical Informatics and Decision Making | Special Issue 3/2020

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Abstract

Background

It is of utmost importance to investigate novel therapies for cancer, as it is a major cause of death. In recent years, immunotherapies, especially those against immune checkpoints, have been developed and brought significant improvement in cancer management. However, on the other hand, immune checkpoints blockade (ICB) by monoclonal antiboties may cause common and severe adverse reactions (ADRs), the cause of which remains largely undetermined. We hypothesize that ICB-agents may induce adverse reactions through off-target protein interactions, similar to the ADR-causing off-target effects of small molecules. In this study, we propose a hybrid phenotype mining approach which integrates molecular level information and provides new mechanistic insights for ICB-associated ADRs.

Methods

We trained a conditional random fields model on the TAC 2017 benchmark training data, then used it to extract all drug-centric phenotypes for the five anti-PD-1/PD-L1 drugs from the drug labels of the DailyMed database. Proteins with structure similar to the drugs were obtained by using BlastP, and the gene targets of drugs were obtained from the STRING database. The target-centric phenotypes were extracted from the human phenotype ontology database. Finally, a screening module was designed to investigate off-target proteins, by making use of gene ontology analysis and pathway analysis.

Results

Eventually, through the cross-analysis of the drug and target gene phenotypes, the off-target effect caused by the mutation of gene BTK was found, and the candidate side-effect off-target site was analyzed.

Conclusions

This research provided a hybrid method of biomedical natural language processing and bioinformatics to investigate the off-target-based mechanism of ICB treatment. The method can also be applied for the investigation of ADRs related to other large molecule drugs.
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Metadata
Title
Hybrid phenotype mining method for investigating off-target protein and underlying side effects of anti-tumor immunotherapy
Authors
Yuyu Zheng
Xiangyu Meng
Pierre Zweigenbaum
Lingling Chen
Jingbo Xia
Publication date
01-07-2020
Publisher
BioMed Central
DOI
https://doi.org/10.1186/s12911-020-1105-4

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