Anti-tumor activity of the MDM2-TP53 inhibitor BI-907828 in dedifferentiated liposarcoma patient-derived xenograft models harboring MDM2 amplification
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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BI-907828 is an orally effective MDM2 inhibitor developed by BI with potential antitumor activity.
“BI-907828 (151) is an orally effective MDM2 inhibitor developed by BI with potential antitumor activity.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [407]
Compared to other MDM2 inhibitors, BI-907828's pharmacokinetic properties allow for dose optimization, potentially reducing myelosuppressive side effects.
“Compared to other MDM2 inhibitors, its pharmacokinetic properties allow for dose optimization, potentially reducing myelosuppressive side effects.407,408”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [407]
When taken orally, BI-907828 binds to the MDM2 protein, preventing the binding of the p53 transcription-activated region, thus restoring p53 transcriptional activity which mediates tumor cell apoptosis.
“When taken orally, it binds to the MDM2 protein, preventing the binding of the p53 transcription-activated region, thus restoring p53 transcriptional activity which mediates tumor cell apoptosis.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [407]
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- Authors
- Cornillie, J., Wozniak, A., Li, H., Gebreyohannes, Y. K., Wellens, J., Hompes, D., Debiec-Rychter, M., Sciot, R., & Schöffski, P.
- Affiliations
- Universitair Ziekenhuis Leuven (BE)
- KU Leuven (BE)
- Corresponding author
- Cornillie, J.
- Venue
- Clinical and Translational Oncology
- Published
- 2019-06-14
- Volume
- 22
- Issue
- 4
- Pages
- 546-554
- ISSN
- 1699-048X (ISSN-L)
- 1699-3055
- OpenAlex
- W2951587879
- Cited by
- 56
- References
- 31
- Citations by year
- 2025: 11 · 2024: 12 · 2023: 18 · 2022: 10 · 2021: 3 · 2020: 2
- FWCI
- 2.78
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical & Translational Oncology (publishedVersion)
- PubMed (publishedVersion)
- Lirias (submittedVersion)
- Funders
- Boehringer Ingelheim
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Sarcoma Diagnosis and Treatment
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- dedifferentiated liposarcoma, MDM2 amplification, BI 907828, MDM2 inhibitors, patient-derived xenografts, anticancer activity, doxorubicin, soft tissue sarcoma, tumor growth inhibition, pathological complete response
- MeSH terms
- Animals, Antineoplastic Agents, Doxorubicin, Gene Amplification, Heterocyclic Compounds, 4 or More Rings, Humans, Liposarcoma, Organic Chemicals, Spiro Compounds, Tumor Suppressor Protein p53, Gene Dosage, Xenograft Model Antitumor Assays, Mice, Proto-Oncogene Proteins c-mdm2
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