Bill Kate Lynn J, Garnett Jeannine, Meaux Isabelle, Ma XiaoYen, Creighton Chad J, Bolshakov Svetlana, Barriere Cedric, Debussche Laurent, Lazar Alexander J, Prudner Bethany C, Casadei Lucia, Braggio Danielle, Lopez Gonzalo, Zewdu Abbie, Bid Hemant, Lev Dina, Pollock Raphael E
The Sarcoma Research Center, The University of Texas MD Anderson Cancer Center, Houston, Texas. The University of Texas Graduate School of Biomedical Sciences, Houston, Texas. Department of Surgical Oncology, Comprehensive Cancer Center, The Ohio State University (OSU), Columbus, Ohio.
The Sarcoma Research Center, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Clin Cancer Res. 2016 Mar 1;22(5):1150-60. doi: 10.1158/1078-0432.CCR-15-1522. Epub 2015 Oct 16.
Dedifferentiated liposarcoma (DDLPS) is an aggressive malignancy that can recur locally or disseminate even after multidisciplinary care. Genetically amplified and expressed MDM2, often referred to as a "hallmark" of DDLPS, mostly sustains a wild-type p53 genotype, substantiating the MDM2:p53 axis as a potential therapeutic target for DDLPS. Here, we report on the preclinical effects of SAR405838, a novel and highly selective MDM2 small-molecule inhibitor, in both in vitro and in vivo DDLPS models.
The therapeutic effectiveness of SAR405838 was compared with the known MDM2 antagonists Nutlin-3a and MI-219. The effects of MDM2 inhibition were assessed in both in vitro and in vivo. In vitro and in vivo microarray analyses were performed to assess differentially expressed genes induced by SAR405838, as well as the pathways that these modulated genes enriched.
SAR405838 effectively stabilized p53 and activated the p53 pathway, resulting in abrogated cellular proliferation, cell-cycle arrest, and apoptosis. Similar results were observed with Nutlin-3a and MI-219; however, significantly higher concentrations were required. In vitro effectiveness of SAR405838 activity was recapitulated in DDLPS xenograft models where significant decreases in tumorigenicity were observed. Microarray analyses revealed genes enriching the p53 signaling pathway as well as genomic stability and DNA damage following SAR405838 treatment.
SAR405838 is currently in early-phase clinical trials for a number of malignancies, including sarcoma, and our in vitro and in vivo results support its use as a potential therapeutic strategy for the treatment of DDLPS.
去分化脂肪肉瘤（DDLPS）是一种侵袭性恶性肿瘤，即使经过多学科治疗仍可局部复发或扩散。基因扩增并表达的MDM2，通常被称为DDLPS的“标志”，大多维持野生型p53基因型，证实MDM2:p53轴是DDLPS的一个潜在治疗靶点。在此，我们报告一种新型且高度选择性的MDM2小分子抑制剂SAR405838在体外和体内DDLPS模型中的临床前效应。
将SAR405838的治疗效果与已知的MDM2拮抗剂Nutlin-3a和MI-219进行比较。在体外和体内评估MDM2抑制的效果。进行体外和体内微阵列分析以评估由SAR405838诱导的差异表达基因，以及这些调控基因富集的途径。
SAR405838有效地稳定了p53并激活了p53途径，导致细胞增殖被抑制、细胞周期停滞和细胞凋亡。Nutlin-3a和MI-219也观察到类似结果；然而，需要显著更高的浓度。在DDLPS异种移植模型中再现了SAR405838活性的体外有效性，其中观察到致瘤性显著降低。微阵列分析显示，SAR405838治疗后，p53信号通路以及基因组稳定性和DNA损伤相关基因富集。
SAR405838目前正在针对包括肉瘤在内的多种恶性肿瘤进行早期临床试验，我们的体外和体内结果支持将其用作治疗DDLPS的潜在治疗策略。
