Research interests

• biology of cancer
• new anticancer therapies
• virtual microscopy

Fig. Metastatic carcinoma cells in a sentinel lymph node detected by an
ultrarapid IHC assay (© J.Isola)

Trastuzumab is a recombinant monoclonal antibody drug that is widely used for the treatment of breast cancer. Despite encouraging clinical results, some cancers are primarily resistant to trastuzumab, and a majority of those initially responding become resistant during prolonged treatment. We have previously established an experimental research model for trastuzumab resistance (cell line JIMT-1) by using cells from a drug-resistant patient. JIMT-1 cells are intrinsically resistant to trastuzumab in vitro, but the direct mechanism(s) for drug resistance remain unclear, despite of numerous published reports by our and other groups.

Although it has been firmly documented that trastuzumab inhibits mitotic and apoptotic signaling via cell surface receptor tyrosine kinases, an increasing number of studies suggest that the main mechanism of action is mediated by the lymphocytic immune reaction evoked by trastuzumab bound on the cancer cells. We have recently shown that immune effector cells (mainly natural killer T lymphocytes) react equally well on breast cancer cell lines irrespective of the direct resistance on mitotic cell signaling, (Barok et al. 2007). The immune-mechanisms are likely to be more important in the treatment of early (submacroscopic but disseminated) cancer, which is the best target for anti-HER2 therapy. We aim to monitor CTCs and DTCs in our xenograft mouse tumor models, and study whether trastuzumab has inhibitory effect on CTCs and DTCs at a time when the primary tumor has already grown too large to be growth-inhibited by trastuzumab and the immune system. According to our hypothesis single tumor cells shed into the blood stream may differ in their trastuzumab sensitivity, since there are no surrounding connective tissue glycosaminoglycans and/or other cell surface molecules responsible for epitope masking. These studies aim at forming experimental basis for molecular diagnostics of circulating HER-2 positive tumors cells.

Main collaborators: Univ Helsinki Dept Oncology (prof. Joensuu), Univ Lund Dept Oncology, Univ Debrecen (Hungary)

Funding: The Finnish Cancer Foundation, the Sigrid Juselius Foundation, and the Medical Research Fund of Tampere University Hospital (EVO)