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Oncotarget. 2018 May 1;9(33):23289-23305. doi: 10.18632/oncotarget.25289. eCollection 2018 May 1.

Treatment of ovarian cancer by targeting the tumor stem cell-associated carbohydrate antigen, Sialyl-Thomsen-nouveau.

Author information

1
Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, USA.
2
Harvard Medical School, Boston, MA, USA.
3
Siamab Therapeutics, Inc., Newton, MA, USA.
4
Division of Gynecologic Oncology, Vincent Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, USA.

Abstract

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.

KEYWORDS:

antibody-drug conjugate; cancer stem cell; ovarian cancer; sialyl-Tn; tumor-associated carbohydrate antigen

Conflict of interest statement

CONFLICTS OF INTEREST Rosemary Foster, Silvia Fatima Hernandez, Linah Al-Alem, Chiara Bellio, Bianca Zarrella, Whitfield B. Growdon, and Kristen Starbuck have no conflicts of interest. Bo Rueda receives stock options for serving as a member of the scientific advisory committee for Siamab Therapeutics, Inc. David Eavarone, Jillian Prendergast, Jenna Stein, Daniel Dransfield and Jeffery Behrens are all employed by Siamab Therapeutics, Inc. This research may lead to the development of products which may be owned by and/or licensed to Siamab Therapeutics, Inc. in which they have a business and/or financial interest.

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