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Anti-tumor activity of the MDM2-TP53 inhibitor BI-907828 in dedifferentiated liposarcoma patient-derived xenograft models harboring MDM2 amplification.
Cornillie, J; Wozniak, A; Li, H; Gebreyohannes, Y K; Wellens, J; Hompes, D; Debiec-Rychter, M; Sciot, R; Schöffski, P.
Afiliação
  • Cornillie J; 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. jasmien.cornillie@uzleuven.be.
  • Wozniak A; 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.
  • Li H; 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.
  • Gebreyohannes YK; 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.
  • Wellens J; 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.
  • Hompes D; Department of Surgical Oncology, KU Leuven and University Hospitals Leuven, Leuven, Belgium.
  • Debiec-Rychter M; Department of Human Genetics, KU Leuven and University Hospitals Leuven, Leuven, Belgium.
  • Sciot R; Department of Pathology, KU Leuven and University Hospitals Leuven, Leuven, Belgium.
  • Schöffski P; 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.
Clin Transl Oncol ; 22(4): 546-554, 2020 Apr.
Article em En | MEDLINE | ID: mdl-31201607
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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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Compostos Orgânicos / Amplificação de Genes / Proteína Supressora de Tumor p53 / Proteínas Proto-Oncogênicas c-mdm2 / Lipossarcoma / Antineoplásicos Limite: Animals / Humans Idioma: En Revista: Clin Transl Oncol Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Bélgica País de publicação: Itália
Texto completo
Adicionar na Minha BVS
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PubMed Links
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Compostos Orgânicos / Amplificação de Genes / Proteína Supressora de Tumor p53 / Proteínas Proto-Oncogênicas c-mdm2 / Lipossarcoma / Antineoplásicos Limite: Animals / Humans Idioma: En Revista: Clin Transl Oncol Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Bélgica País de publicação: Itália