Abstract
Central nervous system germ cell tumors (CNS GCTs) are rare intracranial malignancies developing in adolescents and young adults which relatively frequently occur in East Asia region of the world including Japan. However, among CNS GCTs, non-germinomatous germ cell tumors (NGGCTs) are highly resistant to the current chemoradiotherapies, and the prognosis of CNS NGGCTs is still extremely poor. Therefore, development of novel therapeutic strategy against CNS NGGCTs is urgently needed. In this study, we screened small molecule inhibitors of kinases specifically targeting cell membrane receptors, such as receptor tyrosine kinases, and their related molecular signaling, which could effectively exert antitumor effects against NGGCT cells. As the NGGCT model cells, the Tcam2 cell, a mixed germ cell tumor cell line composed of germinoma and embryonal carcinoma components, and the YST1 cell, a novel yolk sac tumor cell line established in our institute, were used. As a result, effective induction of cell death in both cell lines was confirmed only by treatment with two multi-kinase inhibitors. Immunoblotting revealed these multi-kinase inhibitors suppressed activation of various kinases concurrently. Furthermore, these multi-kinase inhibitors also triggered cell death in the Tcam2 cell stably expressing mutant KIT, the most common oncogenic driver genes of CNS GCTs, suggesting that these inhibitors would be also effective against CNS GCTs harboring activated KIT mutants. In vivo studies of these multi-kinase inhibitors using CNS GCT xenografts are currently on going.