Cervical carcinomas that overexpress human trophoblast cell-surface marker (Trop-2) are highly sensitive to the antibody-drug conjugate sacituzumab govitecan

Authors

Burak Zeybek, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, 06510, USA.
Aranzazu Manzano, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, 06510, USA.
Anna Bianchi, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, 06510, USA.
Elena Bonazzoli, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, 06510, USA.
Stefania Bellone, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, 06510, USA.
Natalia Buza, Department of Pathology, Yale University School of Medicine, 06510, New Haven, CT, USA.
Pei Hui, Department of Pathology, Yale University School of Medicine, 06510, New Haven, CT, USA.
Salvatore Lopez, Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, 88100, Italy.
Emanuele Perrone, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, 06510, USA.
Paola Manara, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, 06510, USA.
Luca Zammataro, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, 06510, USA.
Gary Altwerger, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, 06510, USA.
Chanhee Han, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, 06510, USA.
Joan Tymon-Rosario, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, 06510, USA.
Gulden Menderes, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, 06510, USA.
Elena Ratner, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, 06510, USA.
Dan-Arin Silasi, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, 06510, USA.
Gloria S. Huang, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, 06510, USA.
Masoud Azodi, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, 06510, USA.
Peter E. Schwartz, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, 06510, USA.
Alessandro Santin, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, 06510, USA. alessandro.santin@yale.edu.

Document Type

Article

Publication Title

Scientific reports

Abstract

Human trophoblast cell-surface marker (Trop-2) is a surface glycoprotein originally identified in human placental tissue and subsequently found to be highly expressed by various types of human epithelial solid tumors. We investigated the efficacy of sacituzumab govitecan, an antibody-drug conjugate (ADC) comprised of a humanized anti- Trop-2 antibody, conjugated with active metabolite of irinotecan (SN-38), on Trop-2 positive cervical cancer cell lines and a xenograft model. Trop-2 expression was evaluated in 147 primary cervical tumors by immunohistochemistry, real-time polymerase chain reaction, and flow cytometry. For in vitro experiments, two Trop-2 positive (CVX-8, ADX-3), and one Trop-2 negative (ADX-2) cell lines were used. A cell line with a strong Trop-2 expression (CVX-8) was used to test in vivo antitumor activity in xenografts models. Out of 147 primary cervical cancers, 113 were squamous cell carcinomas (SCCs), and 34 were adenocarcinoma/adenosquamous carcinomas. Moderate to strong diffuse staining was seen in 95% (108/113) of SCCs, and 81% (29/34) of adenocarcinoma/adenosquamous cancers on immunohistochemistry. Trop-2 positive cell lines were highly sensitive to sacituzumab govitecan in vitro, with IC values in the range of 0.18 to 0.26 nM (p = 0.02, and p = 0.04 for CVX-8, and ADX-3, respectively). In xenografts, a significant tumor growth inhibition was seen after twice-weekly intravenous administration of the drug for three weeks (p < 0.0001, and p = 0.001 for sacituzumab govitecan vs naked antibody, and sacituzumab govitecan vs control-ADC, respectively). Overall survival at 90 days was significantly improved in the sacituzumab govitecan group (p = 0.014). In conclusion, sacituzumab govitecan may represent a novel targeted therapy option in cervical cancer patients overexpressing Trop-2.

First Page

973

DOI

10.1038/s41598-020-58009-3

Publication Date

1-22-2020

Recommended Citation

Zeybek, Burak; Manzano, Aranzazu; Bianchi, Anna; Bonazzoli, Elena; Bellone, Stefania; Buza, Natalia; Hui, Pei; Lopez, Salvatore; Perrone, Emanuele; Manara, Paola; Zammataro, Luca; Altwerger, Gary; Han, Chanhee; Tymon-Rosario, Joan; Menderes, Gulden; Ratner, Elena; Silasi, Dan-Arin; Huang, Gloria S.; Azodi, Masoud; Schwartz, Peter E.; and Santin, Alessandro, "Cervical carcinomas that overexpress human trophoblast cell-surface marker (Trop-2) are highly sensitive to the antibody-drug conjugate sacituzumab govitecan" (2020). Obstetrics and Gynecology. 74.
https://scholar.bridgeporthospital.org/obgyn/74

Identifier

31969666 (pubmed); PMC6976591 (pmc); 10.1038/s41598-020-58009-3 (doi); 10.1038/s41598-020-58009-3 (pii)