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Translational Therapeutics

CBL0137 increases the targeting efficacy of Rovalpituzumab tesirine against tumour-initiating cells in small cell lung cancer

Abstract

Small cell lung cancer (SCLC) is characterised by high relapse rates. Tumour-initiating cells (TICs) are responsible for drug resistance and recurrence of cancer. Rovalpituzumab tesirine (Rova-T), a potent humanised antibody–drug conjugate, selectively targets delta-like protein 3, which is highly expressed in SCLC TICs. The experimental drug CBL0137 (CBL) inhibits the histone chaperone FACT (facilitates chromatin transcription), which is required for the expression of transcription factors that are essential for TIC maintenance. Rova-T and CBL each target SCLC TICs as single agents. However, acquired or intrinsic resistance to single agents is a major problem in cancer. Therefore, we investigated the potential effect of combining Rova-T and CBL in SCLC to eradicate TICs more effectively. Our preclinical studies report a novel and highly translatable therapeutic strategy of dual targeting TICs using Rova-T in combination with CBL to potentially increase survival of SCLC patients.

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Fig. 1: Anti-tumour efficacy of combining Rova-T and CBL in vitro and in vivo.

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Acknowledgements

We are extremely thankful to Drs. Andrei Gudkov and Andrei A. Purmal of Incuron Inc. for providing CBL0137. We would like to thank AbbVie Inc. for providing Rova-T, and Dr. Shawn Jeffries, the clinical director of AbbVie, for his support and scientific input. We appreciate the technical support of the Cleveland Clinic Flow Cytometry Core.

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Authors

Contributions

D.J.L. and Y.P. performed the in vivo experiments and S.D. the in vitro experiments. D.J.L., G.W., A.D, G.R.S. and S.D. were involved in designing the study, obtaining research materials and editing the paper. S.D. supervised the study and wrote the initial manuscript.

Corresponding author

Correspondence to Sarmishtha De.

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Ethics approval and consent to participate

All animal experiments were approved by the Cleveland Clinic Foundation Institutional Animal Care and Use Committee and conducted in accordance with the National Institute of Health (NIH) Guide for the Care and Use of Laboratory Animals (Protocol Number: 2017-1863). The cell lines used in this study were obtained from ATCC.

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Not applicable.

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All data generated or analysed during this study are included in this article and its supplementary information files.

Competing interests

The authors declare no competing interests.

Funding information

This research was mainly supported by a Concept Grant (LC170491) from the US Department of Defense (DoD) to S.D. Studies were supported, in part, by the Case Comprehensive Cancer Center Athymic Animal and Xenograft Core and NCI core grant P30 CA043703-23.

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Lindner, D.J., Wildey, G., Parker, Y. et al. CBL0137 increases the targeting efficacy of Rovalpituzumab tesirine against tumour-initiating cells in small cell lung cancer. Br J Cancer 124, 893–895 (2021). https://doi.org/10.1038/s41416-020-01192-x

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