Cornillie J, Wozniak A, Li H, Gebreyohannes Y K, Wellens J, Hompes D, Debiec-Rychter M, Sciot R, 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.
Department of Surgical Oncology, KU Leuven and University Hospitals Leuven, Leuven, Belgium.
Clin Transl Oncol. 2020 Apr;22(4):546-554. doi: 10.1007/s12094-019-02158-z. Epub 2019 Jun 14.
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).
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.
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.
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.
去分化脂肪肉瘤（DDLPS）是一种软组织恶性肿瘤，其特征为小鼠双微体2同源基因（MDM2）扩增。MDM2是肿瘤蛋白53（TP53）的负调节因子。我们在两种DDLPS患者来源异种移植瘤（PDX）中测试了MDM2-TP53相互作用的小分子抑制剂BI-907828的体内疗效。
将部分免疫缺陷小鼠双侧接种携带MDM2扩增的人DDLPS组织UZLX-STS3（n = 24）和UZLX-STS5（n = 24）。小鼠分组如下：（a）载体（0.5%羟乙基纤维素），每天口服（p.o.）10 ml/kg；（b）阿霉素，每周腹腔注射（i.p.）5 mg/kg；（c）BI-907828，每天口服2.5 mg/kg；（d）BI-907828，每天口服10 mg/kg。治疗持续15天，所有接受BI-907828治疗的小鼠在治疗后随访37天。通过肿瘤体积和组织病理学评估疗效。
2.5 mg/kg和10 mg/kg的BI-907828进行15天治疗可显著抑制UZLX-STS5和-STS3中的肿瘤生长（两种模型与对照组相比，p < 0.0001）。所有接受BI-907828治疗的UZLX-STS5和-STS3肿瘤在治疗期间体积均减小，且接受BI-907828治疗的UZLX-STS5肿瘤甚至完全消失。在随访期间，UZLX-STS5模型中未观察到肿瘤复发，两种剂量的BI-907828均导致病理完全缓解，而在UZLX-STS3模型中观察到剂量依赖性复发。
BI-907828在携带MDM2扩增的DDLPS PDX中显示出显著的抗肿瘤活性，为在DDLPS患者群体中对BI-907828进行早期临床试验提供了有力依据。
