Co-Targeting the Notch and EphB4 Receptors in Breast Cancer
|Institution:||University of Southern California|
Debasish Tripathy , M.D. -
|Award Cycle:||2012 (Cycle 18)||Grant #: 18IB-0048||Award: $245,096|
|Innovative Treatments>New drug design: creative science|
Initial Award Abstract (2012)
Currently available breast cancer therapies do not prevent all recurrences after surgery for early stage breast cancer and are not curative in advanced breast cancer, with virtually all patients developing resistance and relapsing over time. Residual breast cancer cells that are resistant to standard therapy are responsible for this problem and we are beginning to understand more about the biological pathways that promote these residual breast cancer cells and the environment within the body that supports them.
Two types of cell receptors, called EphB4 and Notch, “drive” resistant residual cells and their supportive microenvironment. EphB4 and Notch can be targeted with novel biological agents that we have developed. The ephrin family of receptor kinases appears to be involved in the development of the nervous and vascular systems as well as in the regulation of cell shape and movement. The Notch receptor pathway is a key mediator of stem cell maintenance, with several known ligands, of which at least two are tumor and tumor vasculature specific. Interruption of Notch inhibits growth and stromal/tumor interactions in several tumor types and various Notch inhibitors are in early clinical trials. In this project we will test the effect of blocking each and both of the EphB4 and Notch receptor pathways. These pathways are involved in tumor blood vessel formation and the maintenance of immature cancer stem cells that have the ability to repopulate a tumor after response to standard therapy. The EphB4 pathway inhibitor is a fragment of the EphB4 receptor linked to albumin (sEph4-HSA) so that it can block the activation of EphB4 when it binds to stimulator binding proteins call the ligands. The Notch pathway inhibitor is an antibody to two of the ligands (Dll-1 and Dll-4) (MAb61B) that bind and activate Notch, that essentially shuts down the activity of Notch and inhibits both blood vessel formation and the signal to keep stem cells in their undifferentiated state. Human breast cancer cell lines that represent the estrogen and HER2 receptor spectrum will be tested with either of the inhibitors alone and then in combination with both inhibitors and finally, with the addition of chemotherapy. This will be carried out with breast cells in plastic dishes as well as tumors grown in mice. Specific biomarkers will be analyzed on tumor cells and animal tumors to verify that the targets are being modulated and growth is suppressed.
This project is based on elegant and rather new findings on the biology of stem cells and the tumor microenvironment, particularly tumor-related blood vessels. The ultimate of this line of investigation is to develop a new class of therapies that targets residual resistant breast cancer and lead to much better results, possibly even cures in the metastatic setting, when added to standard breast cancer medical treatments.