Anti-tumor activity of the MDM2-TP53 inhibitor BI-907828 in dedifferentiated liposarcoma patient-derived xenograft models harboring MDM2 amplification
Anti-tumor activity of the MDM2-TP53 inhibitor BI-907828 in dedifferentiated liposarcoma patient-derived xenograft models harboring MDM2 amplification
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DOI：
10.1007/s12094-019-02158-z
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发表时间：
2020-04-01
影响因子：
3.4
通讯作者：
Schoffski, P.
中科院分区：
文献类型：
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作者：
Cornillie, J.;Wozniak, A.;Schoffski, P.
目的去分化脂肪肉瘤（Dedifferentiated liposarcoma， DDLPS）是以小鼠双分钟2同源基因（MDM2）扩增为特征的软组织恶性肿瘤。MDM2是肿瘤蛋白53 （TP53）的负调节因子。我们测试了BI-907828（一种MDM2-TP53相互作用的小分子抑制剂）在两例DDLPS患者来源的异种移植物（PDX）中的体内疗效。方法局部免疫缺陷小鼠双侧分别植入含有MDM2扩增的人DDLPS组织UZLX-STS3 （n = 24）和UZLX-STS5 （n = 24）。小鼠按以下方法分组：(a)载药（0.5%羟乙基纤维素）10 ml/kg daily / os (p.o.)；(b)每周腹腔注射阿霉素5mg /kg；(c) BI-907828 2.5 mg/kg / d, (d) BI-907828 10 mg/kg / d，给药15 d，给药后随访37 d。通过肿瘤体积和组织病理学评估疗效。结果2.5 mg/kg和10 mg/kg BI-907828治疗15 d后，与对照组相比，显著抑制了UZLX-STS5和-STS3的肿瘤生长（p < 0.0001）。BI-907828治疗的UZLX-STS5和-STS3肿瘤在治疗过程中均缩小，BI-907828治疗的UZLX-STS5肿瘤甚至完全消失。在随访期间，在UZLX-STS5模型中未观察到肿瘤再生，两种剂量的BI-907828均导致病理完全缓解，而在UZLX-STS3模型中则观察到剂量依赖性的肿瘤再生。结论BI-907828在MDM2扩增的DDLPS PDX中具有明显的抗肿瘤活性，为BI-907828在DDLPS患者群体中的早期临床试验提供了强有力的依据。
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.