Summary of Her2 positive manuscript
In breast cancer, patient prognosis and therapeutic decision are conventionally based on clinicopathological variables such as tumour size, tumour grade and nodal status together with immunohistochemistry biomarkers, such us estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 (Her2). The Her2 positive subtype (Her2+) is frequently associated with invasion and metastasis. Trastuzumab is the first clinically used humanized monoclonal antibody used for targeting overexpressed Her2 receptors. Although new molecules are currently used for targeted therapy in Her2+ patients, the toxicities of Her2 targeted therapies and the development of resistance to treatment challenge clinicians and researchers to search for novel and efficient treatment options by developing drugs with higher efficiency and by decreasing overall dose via targeted therapy. Aiming to restore sensitivity to trastuzumab in trastuzumab resistant Her2+ clones (obtained at the Regional Institute of Oncology during the progress of the current grant) or in a trastuzumab non-responsive cell line, we have linked trastuzumab to the previously developed micelles (developed during the present grant) in order to target cancer cells overexpressing Her2. Our initial in vitro investigations using a responsive cell line revealed that, linking trastuzumab to micelles not only preserves therapeutical effects of trastuzumab but, in addition, seems to enhance this effect. Extending our investigations aiming to demonstrate if linking Tzm to micelles potentiates or not the therapeutical effects of Tzm, we have used additional Her2+ cell lines, responsive, intermediate-responsive and non-responsive to trastuzumab. Cell culture and animal model investigations revealed that there is a double mechanism of acquiring resistance, by increasing Axl expression (expression level and the percentage of Axl positive cells) and by modulating Her2 expression. Cancer cell form two distinct populations based on Her2 expression, one become Her2 negative which is not targeted efficiently by free trastuzumab, and one that express even more Her2. The release of Axl inhibitor loaded into functionalized micelles restores the terapeutical effects of trastuzumab in resistant clone.