gms | German Medical Science

Objective: Eag1, a voltage-gated potassium channel is expressed in the brain and participates in the control of cell excitability. In addition, it has been implicated in malignant transformation and progression in cancer cell lines and human malignancies. Eag1 function can be blocked in vitro and in vivo by monoclonal antibodies or drugs, such as tricyclic antidepressants. We have investigated the expression of Eag1 in brain metastases and the relevance of drug-induced blocking on patient survival.

Method: 75 patients with brain metastases from different cancers, who had undergone surgery and radiotherapy were analyzed. 23/75 patients were also treated with antidepressants because of an endogenous depression (MetDep cohort), 52/75 patients (Met cohort) were not. Formalin-fixed, paraffin-embedded tumor samples were investigated by immunohistochemistry. A recombinant single chain, alkaline phosphatase-fused antibody with epitope located close to the putative pore region was used. The immunohistochemical Eag1 localization was achieved using an alkaline-phosphatase substrate and fast red counterstain. A semi-quantitative microscopic analysis was performed using a four-grade score based on the HercepTest™ assay and validated by two independent observers. Statistical analysis was performed by using t-test and Manova variance analysis (significance level, p<0.05).

Results: Eag1 staining was positive in 78% of the tumors in the MetDep group and in 88% in the Met group, respectively. In the MetDep group, patients displaying a low Eag1 expression (n=11) had a mean survival time of 13.5 months, whereas patients with a high Eag1 expression (n=12) showed a shorter mean survival time of 7.2 months (p=0.05). The significance level was even higher when comparing MetDep low Eag1 expression patients with Met high Eag1 expression patients (p=0.04). The survival impact was more marked in patients treated with Amitriptylin and Citalopram screening a low Eag1 expression (n=9), thus showing a longer survival time of 14.7 months compared to patients in the Met group with high Eag1 expression (n=27), who survived 7.7 months (p=0.013).

Conclusions: Our analyses show that a low expression level of Eag1 is significantly associated with a longer survival time in brain metastases patients. Furthermore, the drug-induced blocking of Eag1 was significantly related to a longer survival time. These results provide a proof for the concept which supports the value of antagonistic monoclonal antibodies against Eag1 in the tailored therapy of brain metastases patients.