Preclinical activity of sacituzumab govitecan (IMMU-132) in uterine and ovarian carcinosarcomas

Salvatore Lopez, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA.
Emanuele Perrone, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA.
Stefania Bellone, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA.
Elena Bonazzoli, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA.
Burak Zeybek, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA.
Chanhee Han, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA.
Joan Tymon-Rosario, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA.
Gary Altwerger, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA.
Gulden Menderes, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA.
Anna Bianchi, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA.
Luca Zammataro, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA.
Aranzazu Manzano, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA.
Paola Manara, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA.
Elena Ratner, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA.
Dan-Arin Silasi, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA.
Gloria S. Huang, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA.
Masoud Azodi, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA.Follow
Peter E. Schwartz, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA.
Francesco Raspagliesi, Department of Gynecologic Oncology, IRCCS National Cancer Institute, Milan, Italy.
Roberto Angioli, University Campus Bio Medico of Rome, Department of Obstetrics and Gynecology, Rome, Italy.
Natalia Buza, Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
Pei Hui, Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
Heather M. Bond, Department of Clinical and Experimental Medicine, Laboratory of Molecular Haematopoiesis and Stem Cell Biology, University "Magna Græcia", Catanzaro, Italy.
Alessandro D. Santin, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA.

Document Type

Article

Publication Title

Oncotarget

Abstract

BACKGROUND: 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. METHODS: 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 in vivo antitumor activity of SG was tested in xenografts models (ie, SARARK9) with strong Trop-2 expression. RESULTS: 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 in vitro 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). CONCLUSION: SG may represent a novel class of active drugs for carcinosarcomas patients overexpressing Trop-2.

First Page

560

Last Page

570

DOI

10.18632/oncotarget.27342

Publication Date

2-4-2020

Identifier

32082489 (pubmed); PMC7007291 (pmc); 10.18632/oncotarget.27342 (doi); 27342 (pii)

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