Oncotarget

Research Papers:

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

Salvatore Lopez, Emanuele Perrone, Stefania Bellone, Elena Bonazzoli, Burak Zeybek, Chanhee Han, Joan Tymon-Rosario, Gary Altwerger, Gulden Menderes, Anna Bianchi, Luca Zammataro, Aranzazu Manzano, Paola Manara, Elena Ratner, Dan-Arin Silasi, Gloria S. Huang, Masoud Azodi, Peter E. Schwartz, Francesco Raspagliesi, Roberto Angioli, Natalia Buza, Pei Hui, Heather M. Bond and Alessandro D. Santin

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Abstract

Salvatore Lopez1,2,3, Emanuele Perrone1, Stefania Bellone1, Elena Bonazzoli1, Burak Zeybek1, Chanhee Han1, Joan Tymon-Rosario1, Gary Altwerger1, Gulden Menderes1, Anna Bianchi1, Luca Zammataro1, Aranzazu Manzano1, Paola Manara1, Elena Ratner1, Dan-Arin Silasi1, Gloria S. Huang1, Masoud Azodi1, Peter E. Schwartz1, Francesco Raspagliesi3, Roberto Angioli4, Natalia Buza5, Pei Hui5, Heather M. Bond6 and Alessandro D. Santin1

1 Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA

2 Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy

3 Department of Gynecologic Oncology, IRCCS National Cancer Institute, Milan, Italy

4 University Campus Bio Medico of Rome, Department of Obstetrics and Gynecology, Rome, Italy

5 Department of Pathology, Yale University School of Medicine, New Haven, CT, USA

6 Department of Clinical and Experimental Medicine, Laboratory of Molecular Haematopoiesis and Stem Cell Biology, University “Magna Græcia”, Catanzaro, Italy

Correspondence to:

Alessandro D. Santin,email: alessandro.santin@yale.edu

Keywords: sacituzumab govitecan; IMMU-132; uterine carcinosarcoma; trop-2

Received: July 19, 2019     Accepted: October 26, 2019     Published: February 04, 2020

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.


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