Therapeutic strategies to overcome tumor heterogeneity in HER2 positive mammary carcinoma

Target therapy has significantly improved the management and the outcome of different types of tumors, including HER2-positive breast cancers. Nevertheless, overall, target therapy has also shown several limitations over the years, as demonstrated by the significant rate of patients who developed resistance to therapy. This is also true for the monoclonal antibody trastuzumab, the gold standard therapy against HER2-positive breast cancer. Tumor heterogeneity is a key factor in resistance to target therapy. This heterogeneity can be intended as spatial, both within a single tumor and among multiple metastases, and temporal. The goal of this thesis was to find alternative strategies and potential druggable targets to overcome tumor heterogeneity in HER2-positive mammary carcinoma through models able to reproduce multiple traits of HER2-positive breast cancer. The research was addressed towards the study of the HER2-VLP, an anti-HER2 cancer vaccine, and approaches aimed at reinforcing vaccine activity. The ability of immune checkpoint inhibitors to modulate immune response and, directly or indirectly, tumor progression was also investigated. To identify new therapeutic targets against progressed breast cancers, mammary carcinoma cell lines derived from HER2 transgenic mice and patient-derived xenograft (PDX) mice were studied. In these models, tumor progression showed epithelial to mesenchymal transition (EMT) traits and increased stemness. Molecules involved in these processes might become new targets for therapeutic approaches. In addition, tumor progression may be also counteracted by turning off alternative survival circuits to HER2 (e.g., IL6/STAT3/SORBS3 and PHLDA1). Finally, the progression of HER2-positive mammary carcinomas can lead to the loss of HER2 expression and acquisition of a claudin-low phenotype and PDGFR-B expression. Sunitinib was effective in slowing the growth of these HER2-negative tumor cells.