Potential Interplay of the Gatipotuzumab Epitope TA-MUC1 and Estrogen Receptors in Ovarian Cancer.

Sabine Heublein,Sven Mahner,Doris Mayr,Udo Jeschke,Frederik Marmé,Elisa Schmoeckel,Fabian Trillsch,Sabina Page,Aurelia Vattai

doi:10.3390/ijms20020295

Abstract

Anti-tumor efficacy of Gatipotuzumab, a therapeutic antibody targeting Tumor-Associated Mucin-1 (TA-MUC1), in relapsed ovarian cancer (OC) appeared to be rather heterogeneous. Whether adding a second anti-neoplastic drug may augment response towards Gatipotuzumab, has not been elucidated so far. Since it is known that anti-MUC1 antibodies may alter estrogen receptor activity in breast cancer, this potential interplay was investigated in OC. The correlation between TA-MUC1, estrogen receptors (ERs) and another 12 protein markers as well as their correlation with clinico-pathological parameters in 138 ovarian cancer cases was studied. Finally, Gatipotuzumab and 4-Hydroxy-TTamoxifen (4-OHT) as well as the combination of both was tested for its impact on cell viability in COV318, OV-90, OVCAR-3, and SKOV-3 cells. A strong positive correlation between TA-MUC1 and ERs was detected in OC tissue. Those cases missing ERs but staining positive for TA-MUC1 had significantly reduced overall survival. The combination of 4-OHT and Gatipotuzumab significantly reduced cell viability and was more effective than treatment with Gatipotuzumab alone. Co-stimulation with Gatipotuzumab enhanced the efficacy of 4-OHT in OVCAR-3 and SKOV-3. The data suggest an interplay of TA-MUC1 and ERs in OC. Whether the combination of Gatipotuzumab and TTamoxifen may enhance efficacy of either of the two drugs in vivo, or may even translate into a clinically relevant benefit over the respective monotherapies, remains to be investigated.

Highlights

MUC1 is an abundantly expressed transmembrane glycoprotein that undergoes several glyco-modifications during the process of malignant transformation, leading to the exposure of tumor-specific, novel carbohydrate epitopes [1]
This study found the Gatipotuzumab epitope tumor-associated MUC1 (TA-MUC1) to be closely correlated to estrogen receptors (ERs) expression in ovarian cancer (OC) tissue
When OC cell lines were exposed to Gatipotuzumab and Tamoxifen, the combination of both drugs significantly decreased cell viability in all the four cell lines tested and was superior as compared to Gatipotuzumab alone

Summary

Introduction

MUC1 is an abundantly expressed transmembrane glycoprotein that undergoes several glyco-modifications during the process of malignant transformation, leading to the exposure of tumor-specific, novel carbohydrate epitopes [1]. Targeting these neo-epitopes seems to be attractive in terms of generating effective, highly selective, and well tolerated anti-cancer therapeutics. TA-MUC1 is present in a wide variety of cancer entities but virtually absent in normal, non-neoplastic tissue [5,6]. This applies for ovarian cancer (OC) as shown by an earlier study of our group [7]

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Conclusion