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Anti-tumor activity of the MDM2-TP53 inhibitor BI-907828 in dedifferentiated liposarcoma patient-derived xenograft models harboring MDM2 amplification

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Abstract

Purpose

Dedifferentiated liposarcoma (DDLPS) is a soft tissue malignancy characterized by amplification of the mouse double minute 2 homolog (MDM2) gene. MDM2 is a negative regulator of tumor protein 53 (TP53). We tested the in vivo efficacy of BI-907828, a small molecule inhibitor of the MDM2-TP53 interaction, in two DDLPS patient-derived xenografts (PDX).

Methods

Partially immunodeficient mice were bilaterally engrafted with UZLX-STS3 (n = 24) and UZLX-STS5 (n = 24) human DDLPS tissue harboring MDM2 amplifications. Mice were grouped as follows: (a) vehicle (0.5% hydroxyethylcellullose) 10 ml/kg daily per os (p.o.); (b) doxorubicin 5 mg/kg weekly intraperitoneally (i.p.); (c) BI-907828 2.5 mg/kg daily p.o. and (d) BI-907828 10 mg/kg daily p.o. The treatment lasted for 15 days, all mice treated with BI-907828 were followed for 37 days post-treatment. Efficacy was assessed by tumor volume and histopathological evaluation.

Results

The 15-day treatment with 2.5 mg/kg and 10 mg/kg BI-907828 significantly inhibited tumor growth in UZLX-STS5 and -STS3 (p < 0.0001 compared to control for both models). All UZLX-STS5 and -STS3 tumors treated with BI-907828 decreased in size during treatment, and BI-907828-treated UZLX-STS5 tumors even disappeared completely. During the follow-up period, no tumor regrowth was observed in the UZLX-STS5 model and both doses of BI-907828 led to a pathological complete response, whereas a dose-dependent regrowth was seen in the UZLX-STS3 model.

Conclusion

BI-907828 showed significant anti-tumor activity in DDLPS PDX harboring MDM2 amplifications, providing a strong rationale for early clinical testing of BI-907828 in a DDLPS patient population.

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Acknowledgements

Boehringer Ingelheim provided the drug and financial support for the study and was involved in the study design, but not in the collection, analysis and interpretation of data.

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Author notes

  1. J. Cornillie, A. Wozniak both authors contributed equally to this article.

Authors and Affiliations

  1. Laboratory of Experimental Oncology, Department of Oncology and Department of General Medical Oncology, Leuven Cancer Institute, KU Leuven and University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium

    J. Cornillie, A. Wozniak, H. Li, Y. K. Gebreyohannes, J. Wellens & P. Schöffski

  2. Department of Surgical Oncology, KU Leuven and University Hospitals Leuven, Leuven, Belgium

    D. Hompes

  3. Department of Human Genetics, KU Leuven and University Hospitals Leuven, Leuven, Belgium

    M. Debiec-Rychter

  4. Department of Pathology, KU Leuven and University Hospitals Leuven, Leuven, Belgium

    R. Sciot

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  1. J. Cornillie
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Correspondence to J. Cornillie.

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Conflict of interest

P. Schöffski has received institutional support from Boehringer Ingelheim for advisory functions and educational activities.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution at which the studies were conducted.

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Informed consent was obtained from all individual participants included in the study.

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Cornillie, J., Wozniak, A., Li, H. et al. Anti-tumor activity of the MDM2-TP53 inhibitor BI-907828 in dedifferentiated liposarcoma patient-derived xenograft models harboring MDM2 amplification. Clin Transl Oncol 22, 546–554 (2020). https://doi.org/10.1007/s12094-019-02158-z

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