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

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.

Cytoplasmic versus nuclear THR alpha expression determines survival of ovarian cancer patients

“…Because the exclusive expression of the FSHR has already been described by our group as a negative prognosticator in ovarian cancer cases, our finding about enhanced expression of both FSHR and THRα in the nucleus might lead to new treatment strategies for this type of cancer (Lenhard et al 2011). This assumption might also apply for the antibody Gatipotuzumab and its TA-MUC1 epitope (Heublein et al 2019), which showed an inverse correlation to THRα1 and -2 expression either in the nucleus or in the cytoplasm, respectively. In addition, T4 has been shown to promote ovarian cancer cell proliferation via integrin αvβ3.…”

THR alpha and its subtypes alpha1 and alpha2 are prognostic markers for survival of ovarian cancer patients

“…Because the exclusive expression of the FSHR has already been described by our group as a negative prognosticator in ovarian cancer cases, our finding about enhanced expression of both FSHR and THRa in the nucleus might lead to new treatment strategies for this type of cancer [24]. This assumption might also apply for the antibody Gatipotuzumab and its TA-MUC1 epitope [45], which showed an inverse correlation to THRa1 and -2 expression either in the nucleus or in the cytoplasm, respectively.…”

Trace Amine-Associated Receptor 1 (TAAR1) Is a Positive Prognosticator for Epithelial Ovarian Cancer

“…Furthermore, membrane TAAR1 expression correlated with Muc-115D8 (Spearman rho: 0.226, p = 0.013), VU3C6 (Spearman rho: 0.180, p = 0.044) and negatively with Glycodelin A (Spearman rho: −0.223, p = 0.012) as shown in Table S1. Muc-115D8 and VU3C6 are, similarly to HMFG1, VU4H5, and TA-MUC1, Mucin-1 (MUC1) epitopes generated by various glyco-modifications of MUC1 during the process of malignant transformation [29]. MUC1 is a high molecular weight transmembrane glycoprotein expressed at the luminal membrane of many types of physiological epithelial cells [30].…”