Since the discovery of an oncogene encoding a protein kinase, inhibition of its activity has been expected as a magical weapon against cancer and in practice, selective inhibitors of Abl, EGFR, BRAF, etc. have shown great clinical results. However at the same time, the emergence of drug resistance to these targeted therapies has become one of the greatest challenges facing cancer medicine. We have discovered that fibroblasts present in the melanoma microenvironment play an important role in the establishment of a temporary drug-resistant environment “safe haven” for BRAF inhibitors. We have also clarified that organ specificity exists in the response to BRAF inhibitors both clinically and experimentally. These results strongly suggest that we need to take into account the impact of tumor microenvironment on cancer treatment.
Our laboratory considers combining a therapeutic strategy targeting organ-specific tumor microenvironment to medical approach based on cancer genome information as “next generation precision medicine” and aims to clarify the mechanisms of cancer cell modification by tumor microenvironments toward clinical application. Especially we focus on the interactive epigenetic regulation between cancer cells and stromal cells in the central nervous system and its involvement in drug resistance and reconstruction of neuroimmune system. Our goal is to establish innovative treatment strategies for surgically-incurable primary and metastatic brain tumors.
Figure 1. “Safe haven” – A temporary drug-resistant microenvironment against BRAF inhibition, visualized by intravital two-photon microscopy.
Scale = 100 μm
Figure 2. Brain metastastatic lung cancer cells well respond to an EGFR inhibitir, gefitinib, however a small fraction of the cells survive in the brain microenvironment.
Scale = 2.5 mm (large panels) and 100 μm (small panel)