Development of an erbB Antagonist
Abstract
Receptor tyrosine kinases of the erbB family play pivotal roles in growth and differentiation and aberrant activation of these receptors is associated with human cancers. In particular, ErbB-2 dysfunction has been linked to about 30% of breast cancers with poor prognosis. Correspondingly, great efforts are being made to develop therapies that target ErbB pathways. ErbB-2 is activated by the neuregulins in heterodimers with the neuregulin receptors ErbB-3 and ErbB-4. An antagonistic neuregulin that down regulates ErbB signaling could function as an anti-tumor agent. The purpose here is to develop such a factor. In previous work, the Drosophila system was used to demonstrate that an antagonistic neuregulin-like factor could be made by deleting the EGF domain or by insertion of the EGF domain from a natural inhibitor. In this project, a vertebrate neuregulin-1 with an EGF domain deletion (NRG-DELTA-EGF) and a factor with the EGF domain from the inhibitor (NRG: :Aos-EGF) were made. The activity of the factors is being tested in transgenic mice by examining heart defects which are characteristic of neuregulin defects. NRG-DELTA-EGF transgenic embryos show no apparent heart defects, however, data from Drosophila suggest the NRG::Aos-EGF will be a stronger inhibitor. Studies are underway for NRG::Aos-EGF transgenes and will be completed during a one-year no-cost extension of the project.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2002
- Accession Number
- ADA408845
Entities
People
- Amanda A. Simcox
Organizations
- Ohio State University