The studies suggest that either combination or sequential coupling of anti-STn therapy with conventional cytotoxics would target both bulk tumor cells and CSCs that carry the STn antigen to induce a more durable remission without excessive toxicity in OvCa patients.
Bo R. Rueda from Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, the Siamab Therapeutics, Inc., Newton, MA, the Division of Gynecologic Oncology, Vincent Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, and the Harvard Medical School, Boston, MA, USA said "highly glycan-specific anti-STn antibodies conjugated to the cytotoxic drug monomethyl auristatin E (MMAE) as developed in Prendergast et. al, [25] decreased both OvCa cell viability in vitro and OvCa xenograft tumor volume in vivo, supporting our hypothesis that targeting of STn in ovarian tumors may be an effective clinical strategy."
Ov Ca relapse can be explained in part by the persistence of a small subset of tumor cells often called cancer stem cells that are hypothesized to survive adjuvant chemotherapy despite a significant reduction in tumor burden.
Since STn expressing cancers are associated with increased tumor initiation, progression and chemoresistance, it is reasonable to hypothesize that STn is also present on CSC populations, especially since protein CSC markers such as MUC1 and CD44v6 are known carriers of STn.
Figure 1: STn and CD133 are co-expressed in human ovarian cancer cell lines. A representative example of flow cytometric scatter plots for STn and CD133 levels in OV90, OVCAR3 and OVCAR4 cells is shown along with quantification of the four populations analyzed (STn-/CD133-, STn-/CD133+, STn+/CD133- and STn+/CD133+). Error bars represent the mean ± SEM of three independent experiments.
The research team hypothesized that STn+ Ov Ca cells would demonstrate stem cell-like phenotypes compared to STn- cells. Moreover, they postulated that utilizing a highly glycan-specific anti-STn ADC would reduce tumor burden in an in vivo model.
The results demonstrate that the STn antigen is expressed in Ov Ca cell lines and a subset of the STn+ cells co-express the Ov Ca CSC marker CD133. More importantly, highly glycan-specific anti-STn antibodies conjugated to the cytotoxic drug monomethyl auristatin E as developed in Prendergast et. al, decreased both Ov Ca cell viability in vitro and Ov Ca xenograft tumor volume in vivo, supporting our hypothesis that targeting of STn in ovarian tumors may be an effective clinical strategy.
The Rueda research team concluded that "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."
Full text - https://doi.org/10.18632/oncotarget.25289
Correspondence to - Bo R. Rueda - [email protected]
Keywords - ovarian cancer, sialyl-Tn, antibody-drug conjugate, cancer stem cell, tumor-associated carbohydrate antigen
