Co-Targeting HER2 and EphB4 Pathways

摘要

Multiple receptor pathways allow for redundancy in growth pathways that are dysregulated in cancer and lead to resistance to targeted therapies. EphB4 angiogenesis receptor can cooperate with HER2 growth factor signaling, and co-targeting HER2 and EphB4 could lead to significant therapeutic benefits. The goal of the full project is to assess the in vitro and in vivo growth and signaling effects of co-targeting using approved anti-HER2 agents, trastuzumab and lapatinib in combination with an agent that inhibits EphB4 signaling developed by our group, a ligand-blocking soluble albumin-stabilized EphB4 peptide termed sEphB4-HSA. We have determined that Her2 induces EphB4 and EphrinB2 in three different settings including isogenic cell lines with and without Her2 expression, gene expression data sets on human breast cancer tissues from three different cohorts, and in the Her2 trangene expressed in mammary tissue/tumor in mice. We next determined that EphB4 provides survival signal in Her2 positive tumor cell lines in vitro and in ex-vivo human tumor fresh samples. Next we studied in transgenic mouse expressing Her2 in the mammary gland causing spontaneous tumor. Inhibition of EphB4-EphrinB2 with soluble decoy Ephb4 markedly inhibited tumor formation, growth and metastasis. A remarkable novel finding is that blocking EphB4-EphrinB2 interaction with sEphB4 led to marked inhibition of Her2 phosphorylation.