Lopez Salvatore, Perrone Emanuele, Bellone Stefania, Bonazzoli Elena, Zeybek Burak, Han Chanhee, Tymon-Rosario Joan, Altwerger Gary, Menderes Gulden, Bianchi Anna, Zammataro Luca, Manzano Aranzazu, Manara Paola, Ratner Elena, Silasi Dan-Arin, Huang Gloria S, Azodi Masoud, Schwartz Peter E, Raspagliesi Francesco, Angioli Roberto, Buza Natalia, Hui Pei, Bond Heather M, Santin Alessandro D
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA.
Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy.
Oncotarget. 2020 Feb 4;11(5):560-570. doi: 10.18632/oncotarget.27342.
Uterine and ovarian carcinosarcomas (CS) are rare cancers with poor prognosis. Sacituzumab-govitecan (SG) is a new class of antibody-drug-conjugate (ADC) targeting the human-trophoblast-cell-surface marker (Trop-2) conjugated with the active metabolite of irinotecan (SN-38). We evaluated the efficacy of SG against biologically aggressive CS.
Trop-2 expression was evaluated in 10 formalin-fixed-paraffined-embedded (FFPE) CS by immunohistochemistry and 9 primary CS cell-lines by flow-cytometry. One Trop-2 low/negative (SARARK14) and two Trop-2 positive (SARARK4, SARARK9) cell-lines were tested in cell-viability assays . The antitumor activity of SG was tested in xenografts models (ie, SARARK9) with strong Trop-2 expression.
Strong/diffuse staining was seen in 30% (3/10) of FFPE tumors and 33% (3/9) of primary CS cell lines. Trop-2 positive cell-lines (SARARK4, SARARK9) showed higher sensitivity to SG when compared to Trop-2 low/negative (SARARK14) cell lines. In xenografts, twice-weekly intravenous administration of SG for three weeks showed a significant tumor growth inhibition when compared to control, to ADC control and to the naked AB (p=0.004, p=0.007 and p=0.0007, respectively). SG significantly improved overall survival at 90 days when compared to control groups (p<0.0001).
SG may represent a novel class of active drugs for carcinosarcomas patients overexpressing Trop-2.
子宫和卵巢癌肉瘤（CS）是预后较差的罕见癌症。赛托珠单抗-戈维汀（SG）是一类新型的抗体药物偶联物（ADC），靶向人滋养层细胞表面标志物（Trop-2），并与伊立替康的活性代谢产物（SN-38）偶联。我们评估了SG对具有生物学侵袭性的CS的疗效。
通过免疫组织化学在10例福尔马林固定石蜡包埋（FFPE）的CS中评估Trop-2表达，并通过流式细胞术在9个原发性CS细胞系中评估。在细胞活力测定中测试了1个Trop-2低表达/阴性（SARARK14）细胞系和2个Trop-2阳性（SARARK4、SARARK9）细胞系。在具有强Trop-2表达的异种移植模型（即SARARK9）中测试了SG的抗肿瘤活性。
在30%（3/10）的FFPE肿瘤和33%（3/9）的原发性CS细胞系中观察到强/弥漫性染色。与Trop-2低表达/阴性（SARARK14）细胞系相比，Trop-2阳性细胞系（SARARK4、SARARK9）对SG表现出更高的敏感性。在异种移植中，与对照组、ADC对照组和裸抗体相比，每周两次静脉注射SG三周显示出显著的肿瘤生长抑制（分别为p=0.004、p=0.007和p=0.0007）。与对照组相比，SG在90天时显著改善了总生存期（p<0.0001）。
SG可能是一类针对过表达Trop-2的癌肉瘤患者的新型活性药物。
