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OCTAD: an open workspace for virtually screening therapeutics targeting precise cancer patient groups using gene expression features

Nature Protocols volume 16, pages 728–753 (2021)Cite this article

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Abstract

As the field of precision medicine progresses, treatments for patients with cancer are starting to be tailored to their molecular as well as their clinical features. The emerging cancer subtypes defined by these molecular features require that dedicated resources be used to assist the discovery of drug candidates for preclinical evaluation. Voluminous gene expression profiles of patients with cancer have been accumulated in public databases, enabling the creation of cancer-specific expression signatures. Meanwhile, large-scale gene expression profiles of cellular responses to chemical compounds have also recently became available. By matching the cancer-specific expression signature to compound-induced gene expression profiles from large drug libraries, researchers can prioritize small molecules that present high potency to reverse expression of signature genes for further experimental testing of their efficacy. This approach has proven to be an efficient and cost-effective way to identify efficacious drug candidates. However, the success of this approach requires multiscale procedures, imposing considerable challenges to many labs. To address this, we developed Open Cancer TherApeutic Discovery (OCTAD; http://octad.org): an open workspace for virtually screening compounds targeting precise groups of patients with cancer using gene expression features. Its database includes 19,127 patient tissue samples covering more than 50 cancer types and expression profiles for 12,442 distinct compounds. The program is used to perform deep-learning-based reference tissue selection, disease gene expression signature creation, drug reversal potency scoring and in silico validation. OCTAD is available as a web portal and a standalone R package to allow experimental and computational scientists to easily navigate the tool.

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Fig. 1: Systems description.
Fig. 2: OCTAD cancer maps.
Fig. 3: OCTAD compounds.
Fig. 4
Fig. 5: Screen compounds targeting HCC.
Fig. 6: Correlation between sRGES and efficacy data under different parameter values in HCC.
Fig. 7: Evaluation of the results from major steps in HCC prediction.

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Data availability

The data related to this protocol can be found at http://octad.org/download or https://www.synapse.org/#!Synapse:syn22101254. You can also refer to the preprint version of our protocol: https://www.biorxiv.org/content/10.1101/821546v1. This pipeline was verified in our previous research papers.

Software availability

The software is available from http://octad.org/download or https://www.synapse.org/#!Synapse:syn22101254.

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Acknowledgements

The research is supported by R01GM134307, R21 TR001743 and K01 ES028047 and the MSU Global Impact Initiative. Amazon AWS research credits were received to support portal development and hosting. The portal was developed with help from Optra Health and MSU IT. The content is solely the responsibility of the authors and does not necessarily represent the official views of sponsors.

Author information

Author notes

  1. These authors contributed equally: Billy Zeng, Benjamin S. Glicksberg, Patrick Newbury, Evgeny Chekalin.

Authors and Affiliations

  1. Department of Pediatrics and Human Development, Michigan State University, Grand Rapids, MI, USA

    Billy Zeng, Patrick Newbury, Evgeny Chekalin, Jing Xing, Ke Liu & Bin Chen

  2. Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, USA

    Billy Zeng, Benjamin S. Glicksberg & Caven Chow

  3. The Hasso Plattner Institute for Digital Health at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Benjamin S. Glicksberg

  4. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Benjamin S. Glicksberg

  5. Department of Pharmacology and Toxicology, Michigan State University, Grand Rapids, MI, USA

    Evgeny Chekalin, Jing Xing, Ke Liu & Bin Chen

  6. Department of Nutrition, University of California, Davis, Davis, CA, USA

    Anita Wen

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Contributions

B.Z. led the project, developed the desktop version and wrote the manuscript. B.S.G. and P.N. co-led the project, coordinated web portal development and wrote the manuscript. E.C. developed the R package, led the revision and wrote the manuscript. J.X. performed the LINCS compound analysis, developed compound enrichment analysis and tested the desktop package. K.L. implemented the Toil pipeline and processed RNA-Seq samples. A.W. helped develop the code, prepared tutorials and created case studies. C.C. helped with troubleshooting. B.C. developed the initial code, wrote the manuscript and supervised the project.

Corresponding author

Correspondence to Bin Chen.

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The authors declare no competing interests.

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Peer review information Nature Protocols thanks the anonymous reviewers for their contribution to the peer review of this work.

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Key references using this protocol

Chen, B. et al. Nat. Commun. 8, 16022 (2017): https://doi.org/10.1038/s41467-019-10148-6

Chen, B. et al. Gastroenterology 152, 2022–2036 (2017): https://doi.org/10.1053/j.gastro.2017.02.039

Zeng, W. Z. D., Glicksberg, B. S., Li, Y. & Chen, B. BMC Med. Genomics 12, 21 (2019): https://doi.org/10.1186/s12920-018-0463-6

Liu, K. et al. Nat. Commun. 10, 2138 (2019): https://doi.org/10.1038/s41467-019-10148-6

Extended data

Extended Data Fig. 1 Screenshots of the web portal.

(a) Disease sample selection, (b) control sample selection, (c) drug prediction job submission, (e) job management, (f) predicted drug list and (g) result files.

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Supplementary Information

Supplementary Text and Supplementary Figs. 1–5.

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Zeng, B., Glicksberg, B.S., Newbury, P. et al. OCTAD: an open workspace for virtually screening therapeutics targeting precise cancer patient groups using gene expression features. Nat Protoc 16, 728–753 (2021). https://doi.org/10.1038/s41596-020-00430-z

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