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The smac mimetic LCL161 targets established pulmonary osteosarcoma metastases in mice

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Abstract

Osteosarcoma is the most common form of primary bone cancer and frequently metastasizes to the lungs. Current therapies fail to successfully treat over two thirds of patients with metastatic osteosarcoma, so there is an urgent imperative to develop therapies that effectively target established metastases. Smac mimetics are drugs that work by inhibiting the pro-survival activity of IAP proteins such as cIAP1 and cIAP2, which can be overexpressed in osteosarcomas. In vitro, osteosarcoma cells are sensitive to a range of Smac mimetics in combination with TNFα. This sensitivity has also been demonstrated in vivo using the Smac mimetic LCL161, which inhibited the growth of subcutaneous and intramuscular osteosarcomas. Here, we evaluated the efficacy of LCL161 using mice bearing osteosarcoma metastases without the presence of a primary tumor, modeling the scenario in which a patient’s primary tumor had been surgically removed. We demonstrated the ability of LCL161 as a single agent and in combination with doxorubicin to inhibit the growth of, and in some cases eliminate, established pulmonary osteosarcoma metastases in vivo. Resected lung metastases from treated and untreated mice remained sensitive to LCL161 in combination with TNFα ex vivo. This suggested that there was little to no acquired resistance to LCL161 treatment in surviving osteosarcoma cells and implied that tumor microenvironmental factors underlie the observed variation in responses to LCL161.

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All data generated or analyzed during this study are included in this published article.

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Acknowledgements

We thank Margaret Veale and the La Trobe Institute for Molecular Science BioImaging Facility for assistance with flow cytometry and La Trobe Animal Research and Training Facility for assistance with animal experiments. We also thank Novartis for providing the LCL161 used in this study.

Funding

This study was funded by grants from The Kids’ Cancer Project, Cancer Council Victoria and Tour de Cure.

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Authors and Affiliations

  1. Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia

    Michael A. Harris, Tanmay M. Shekhar, Mark A. Miles, Carmelo Cerra & Christine J. Hawkins

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  1. Michael A. Harris
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  2. Tanmay M. Shekhar
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  3. Mark A. Miles
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  4. Carmelo Cerra
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  5. Christine J. Hawkins
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Contributions

MAH, TMS and CJH designed the experiments. MAH, TMS, MAM and CC conducted the experiments. MAH and CJH analyzed the data and wrote the manuscript. CJH supervised the project and provided funding.

Corresponding author

Correspondence to Christine J. Hawkins.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

Animal experiments were conducted in accordance with Australian Code of Practice for the Care and Use of Animals for Scientific Purposes, as approved by the La Trobe Animal Ethics Committee (approval AEC17–76).

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Harris, M.A., Shekhar, T.M., Miles, M.A. et al. The smac mimetic LCL161 targets established pulmonary osteosarcoma metastases in mice. Clin Exp Metastasis 38, 441–449 (2021). https://doi.org/10.1007/s10585-021-10116-9

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  • DOI: https://doi.org/10.1007/s10585-021-10116-9

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