Treatment of ovarian cancer by targeting the tumor stem cell-associated carbohydrate antigen, Sialyl-Thomsen-nouveau
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Kristen Starbuck1,4, Linah Al-Alem1,4, David A. Eavarone2, Silvia Fatima Hernandez1,4, Chiara Bellio1,4, Jillian M. Prendergast2, Jenna Stein2, Daniel T. Dransfield2, Bianca Zarrella1, Whitfield B. Growdon1,3,4, Jeff Behrens2, Rosemary Foster1,3,4,* and Bo R. Rueda1,3,4,*
1Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, USA
2Siamab Therapeutics, Inc., Newton, MA, USA
3Division of Gynecologic Oncology, Vincent Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, USA
4Harvard Medical School, Boston, MA, USA
*These authors have contributed equally to this work
Bo R. Rueda, email: [email protected]
Keywords: ovarian cancer; sialyl-Tn; antibody-drug conjugate; cancer stem cell; tumor-associated carbohydrate antigen
Received: April 04, 2017 Accepted: April 08, 2018 Published: May 1, 2018
Recurrent ovarian cancer (OvCa) is thought to result in part from the inability to eliminate rare quiescent cancer stem cells (CSCs) that survive cytotoxic chemotherapy and drive tumor resurgence. The Sialyl-Thomsen-nouveau antigen (STn) is a carbohydrate moiety present on protein markers of CSCs in pancreatic, colon, and gastric malignancies. We have demonstrated that human OvCa cell lines contain varying levels of cells that independently express either STn or the ovarian CSC marker CD133. Here we determine co-expression of STn and CD133 in a subset of human OvCa cell lines. Analyses of colony and sphere forming capacity and of response to standard-of-care cytotoxic therapy suggest a subset of OvCa STn+ cells display some CSC features. The effect of the anti-STn antibody-drug conjugates (ADCs) S3F-CL-MMAE and 2G12-2B2-CL-MMAE on OvCa cell viability in vitro and in vivo was also assessed. Treatment with S3F-CL-MMAE reduced the viability of two of three OvCa cell lines in vitro and exposure to either S3F-CL-MMAE or 2G12-2B2-CL-MMAE reduced OVCAR3-derived xenograft volume in vivo, depleting STn+ tumor cells. In summary, STn+ cells demonstrate some stem-like properties and specific therapeutic targeting of STn in ovarian tumors may be an effective clinical strategy to eliminate both STn+ CSC and STn+ non-CSC populations.
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