A survey of optimal strategy for signature-based drug repositioning and an application to liver cancer

  1. Chen Yang
  2. Hailin Zhang
  3. Mengnuo Chen
  4. Siying Wang
  5. Ruolan Qian
  6. Linmeng Zhang
  7. Xiaowen Huang
  8. Jun Wang
  9. Zhicheng Liu
  10. Wenxin Qin
  11. Cun Wang  Is a corresponding author
  12. Hualian Hang  Is a corresponding author
  13. Hui Wang  Is a corresponding author
  1. Shanghai Jiao Tong University, China
  2. Huazhong University of Science and Technology, China

Abstract

Pharmacologic perturbation projects, such as Connectivity Map (CMap) and Library of Integrated Network-based Cellular Signatures (LINCS), have produced many perturbed expression data, providing enormous opportunities for computational therapeutic discovery. However, there is no consensus on which methodologies and parameters are the most optimal to conduct such analysis. Aiming to fill this gap, new benchmarking standards were developed to quantitatively evaluate drug retrieval performance. Investigations of potential factors influencing drug retrieval were conducted based on these standards. As a result, we determined an optimal approach for LINCS data-based therapeutic discovery. With this approach, homoharringtonine (HHT) was identified to be a candidate agent with potential therapeutic and preventive effects on liver cancer. The antitumor and antifibrotic activity of HHT was validated experimentally using subcutaneous xenograft tumor model and carbon tetrachloride (CCL4)-induced liver fibrosis model, demonstrating the reliability of the prediction results. In summary, our findings will not only impact the future applications of LINCS data but also offer new opportunities for therapeutic intervention of liver cancer.

Data availability

Sequencing data have been deposited in GEO under accession codes GSE180243 and GSE193897.All data generated or analysed during this study are included in the manuscript and supporting files.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Chen Yang

    Department of Liver Surgery, Shanghai Jiao Tong University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Hailin Zhang

    Department of Liver Surgery, Shanghai Jiao Tong University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Mengnuo Chen

    Department of Liver Surgery, Shanghai Jiao Tong University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Siying Wang

    Department of Liver Surgery, Shanghai Jiao Tong University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Ruolan Qian

    Department of Liver Surgery, Shanghai Jiao Tong University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Linmeng Zhang

    Department of Liver Surgery, Shanghai Jiao Tong University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Xiaowen Huang

    Division of Gastroenterology and Hepatology, Shanghai Jiao Tong University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Jun Wang

    Department of Liver Surgery, Shanghai Jiao Tong University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Zhicheng Liu

    Hepatic Surgery Center, Huazhong University of Science and Technology, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.
  10. Wenxin Qin

    Department of Liver Surgery, Shanghai Jiao Tong University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  11. Cun Wang

    Department of Liver Surgery, Shanghai Jiao Tong University, Shanghai, China
    For correspondence
    cwang@shsci.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4977-2189
  12. Hualian Hang

    Department of Liver Surgery, Shanghai Jiao Tong University, Shanghai, China
    For correspondence
    hanghualian@shsmu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
  13. Hui Wang

    Department of Liver Surgery, Shanghai Jiao Tong University, Shanghai, China
    For correspondence
    hwang@shsci.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4947-9537

Funding

National Natural Science Foundation of China (81972208)

  • Hui Wang

National Natural Science Foundation of China (82170646)

  • Hualian Hang

Shanghai Natural Science Foundation (19ZR1452700)

  • Hui Wang

The Interdisciplinary Program of Shanghai Jiao Tong University (YG2021ZD10)

  • Hualian Hang

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animals were manipulated according to protocols approved by the Shanghai Medical Experimental Animal Care Commission and Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine.

Reviewing Editor

  1. Arduino A Mangoni, Flinders Medical Centre, Australia

Publication history

  1. Preprint posted: June 30, 2021 (view preprint)
  2. Received: July 2, 2021
  3. Accepted: February 16, 2022
  4. Accepted Manuscript published: February 22, 2022 (version 1)
  5. Version of Record published: March 3, 2022 (version 2)

Copyright

© 2022, Yang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Chen Yang
  2. Hailin Zhang
  3. Mengnuo Chen
  4. Siying Wang
  5. Ruolan Qian
  6. Linmeng Zhang
  7. Xiaowen Huang
  8. Jun Wang
  9. Zhicheng Liu
  10. Wenxin Qin
  11. Cun Wang
  12. Hualian Hang
  13. Hui Wang
(2022)
A survey of optimal strategy for signature-based drug repositioning and an application to liver cancer
eLife 11:e71880.
https://doi.org/10.7554/eLife.71880
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    Background:

    Sarcomas comprise approximately 1% of all human malignancies; treatment resistance is one of the major reasons for the poor prognosis of sarcomas. Accumulating evidence suggests that non-coding RNAs (ncRNAs), including miRNAs, long ncRNAs, and circular RNAs, are important molecules involved in the crosstalk between resistance to chemotherapy, targeted therapy, and radiotherapy via various pathways.

    Methods:

    We searched the PubMed (MEDLINE) database for articles regarding sarcoma-associated ncRNAs from inception to August 17, 2022. Studies investigating the roles of host-derived miRNAs, long ncRNAs, and circular RNAs in sarcoma were included. Data relating to the roles of ncRNAs in therapeutic regulation and their applicability as biomarkers for predicting the therapeutic response of sarcomas were extracted. Two independent researchers assessed the quality of the studies using the Würzburg Methodological Quality Score (W-MeQS).

    Results:

    Observational studies revealed the ectopic expression of ncRNAs in sarcoma patients who had different responses to antitumor treatments. Experimental studies have confirmed crosstalk between cellular pathways pertinent to chemotherapy, targeted therapy, and radiotherapy resistance. Of the included studies, W-MeQS scores ranged from 3 to 10 (average score = 5.42). Of the 12 articles that investigated ncRNAs as biomarkers, none included a validation cohort. Selective reporting of the sensitivity, specificity, and receiver operating curves was common.

    Conclusions:

    Although ncRNAs appear to be good candidates as biomarkers for predicting treatment response and therapeutics for sarcoma, their differential expression across tissues complicates their application. Further research regarding their potential for inhibiting or activating these regulatory molecules to reverse treatment resistance may be useful.

    Funding:

    This study’s literature retrieval was supported financially by the 345 Talent Project of Shengjing Hospital of China Medical University (M0949 to Tao Zhang).

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