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, Aránzazu Manzano, Paola Manara, Elena Ratner, Dan‐Arin Silasi, Gloria S. Huang, Masoud Azodi, Peter E. Schwartz, Francesco Raspagliesi, Roberto Angioli, Natália Buza, Pei Hui, Heather M. Bond, Alessandro D. Santin
Abstract
// Salvatore Lopez 1 , 2 , 3 , Emanuele Perrone 1 , Stefania Bellone 1 , Elena Bonazzoli 1 , Burak Zeybek 1 , Chanhee Han 1 , Joan Tymon-Rosario 1 , Gary Altwerger 1 , Gulden Menderes 1 , Anna Bianchi 1 , Luca Zammataro 1 , Aranzazu Manzano 1 , Paola Manara 1 , Elena Ratner 1 , Dan-Arin Silasi 1 , Gloria S. Huang 1 , Masoud Azodi 1 , Peter E. Schwartz 1 , Francesco Raspagliesi 3 , Roberto Angioli 4 , Natalia Buza 5 , Pei Hui 5 , Heather M. Bond 6 and Alessandro D. Santin 1 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: [email protected] 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.