Experimental Oncology (work group 4)

Breast Cancer

Insight into molecular mechanisms of malignant transformation is changing the way cancer is being treated. Conventional treatment strategies target the DNA of all dividing cells, resulting in a significantly increased risk of collateral toxicity. In addition, the accumulation of multiple mutations leads to drug resistance in many cancer cells. Targeted strategies have now been developed that specifically disrupt oncogenically active cell surface receptors and endogenous signalling molecules. The epithelial cell adhesion molecule (Ep-CAM) has emerged as an attractive therapeutic target for patients with breast cancer. Ep-CAM protein overexpression has been described by our group in several human malignancies and was associated with poor prognosis. This effect on tumor behaviour is probably due to increased signaling via the Ep-CAM receptor. In fact, interruption of this process has been shown to cause anti-tumor effects.

Immunotherapy and Breast Cancer

Two major mechanisms of Ep-CAM targeted therapies are available:

– Passive Immunotherapy:
The use of monoclonal antibodies as adjuvants to cancer chemotherapy has drawn considerable interest in recent years, due to the success of several novel agents against a broad range of targets (e.g. Trastuzumab, Bevacizumab, Rituximab, Cetuximab). Anti-tumor responses have been observed in metastatic colorectal cancer after treatment with the Ep-CAM specific monoclonal antibody Edrecolomab. Initial studies of monoclonal antibodies directed against Ep-CAM demonstrated the presence of anti-idiotype networks involving both B and T cells, antibody-dependent cell cytotoxicity, and complement mediated cell death as mechanisms of tumor growth inhibition. Of note, the use of humanized anti-Ep-CAM antibodies (e.g. MT201) is already being tested in clinical trials with metastatic breast cancer patients at our institution.

– Active Immunotherapy:
Further therapeutic approaches consist in using an Ep-CAM specific vaccine (IGN101) inducing an active immune response in patients with cancer of different epithelial origin. This therapeutic approach is beeing tested in patients with Ep-CAM expressing epithelial cancers.
If targeting the Ep-CAM antigen has proven to display antitumor effects, little is known about the precise molecular effects responsible for the anti-tumor activity of these therapeutic agents. Improved molecular characterization and greater understanding of the effects of Ep-CAM expression and targeting strategies will enable a better prediction of the action and potential side effects of this treatment strategy. The elucidation of potential common pathways with those of other therapeutic agents could help in defining additive and even synergistic anti-tumor activity with conventional treatment modalities.