Amy Ferreccio

Interdisciplinary Training

Amy Ferreccio

"Generation of novel, high affinity Tie2 antagonists through protein design to block aggressive cancer cell resistance to radiation and chemotherapy"

Many types of normal and cancer stem cells are resistant to killing by genotoxins, but the
mechanism for this resistance is poorly understood. Ruohola-Baker lab has recently shown that
adult stem cells in Drosophila melanogaster germ line and midgut are resistant to ionizing
radiation (IR) or chemically induced apoptosis by Tie-2 activation due to the ligand secreted
from dying daughters.  We propose that dying daughters send a survival signal to protect their
stem cells for future repopulation of the tissue. If conserved in cancer stem cells, this
mechanism may provide therapeutic options for eradication of cancer. We show that human
embryonic stem cells (hESCs) also obtain a survival signal from the dying feeder cell layer. We
identified Tie-2 as the receptor for this signal and angiopoietin-1 (Ang1) as a signal secreted
from dying cells. Based on our results on Drosophila and hESCs, the Ang1/Tie2 pathway is a very
attractive anti-cancer therapeutic target since in addition to previously shown action in tumor
vascularization it may also regulate cancer stem cell protection by dying cells after radiotherapy
or chemotherapy. My goal is to design novel Tie2 inhibitors (Tie*-fighters) in collaboration with
the Institute for Protein Design (IPD/Baker lab) and then screen the efficacy of the novel Tie*-
fighters in hESCs and further, analyze their mechanism of action. The goal is to generate novel,
high affinity Tie2 antagonists that can be tested in the future in vivo for their effects on tumor
recurrence after irradiation and chemotherapy.