关键词：乳腺癌;血液细胞(生物学);乳腺肿瘤;感觉器官
摘 要：Multiple receptor pathways are often induced in cancer and thus allow redundancy in providing growth and survival advantage to tumor cells. In addition, micro-environment including increased blood perfusion into the tumor can provide advantage to the tumor. EphB4 receptor tyrosine kinase & its ligand EphrinB2 appear to have dual function. EphB4 & its ligand are needed for the formation & maturation of blood vessels. EphB4 in addition is induced in tumor cells, where it may cooperate with HER2 growth factor signaling. Thus co- targeting HER2 & EphB4 could lead to significant therapeutic benefits. The goal of this project is to assess the in vitro and in vivo growth and signaling effects of co-targeting using approved anti-HER2 agents, trastuzumab & lapatinib in combination with an inhibitor of EphB4-EphrinB2, namely soluble EphB4-HSA, which was discovered in our laboratory. The other component of this project is to use genetic models to define the contribution of EphB4 & EphrinB2 in the formation and progression of Her2 positive tumor. In this aim we will use Her2 transgenic mice that develop mammary gland tumors, and cross with the mice in which either EphB4 or EphrinB2 gene is deleted. We have generated or acquired the mouse lines to conduct this part of the project. Lastly we wish to determine if EphB4 is induced in tumors that become resistant to Her2 targeted therapy, and the role of EphB4 in such a case. Can EphB4 targeted therapy reset the clock and sensitize the tumor to her2 targeted therapy. Early evidence indicates that this may be possible. This work & the soon to start Phase I study of soluble EphB4HSA phase I trial at our institution will set the foundation for design of combined targeting Her2 & EphB4 in human trial.