Appointment period: 1/1/2013 to 12/31/2014
Characterization of ErbB Receptors in Nanoparticles
The four members of the ErbB family of mammalian receptor tyrosine kinases play key roles in the development and maintenance of a variety of tissues, and the overexpression and aberrant activation of these receptors actively contribute to the progression of epithelial and brain tumors. Over-expression of ErbB2 has been observed in a significant proportion (25-30%) of breast cancer patient tumors, and is correlated with poor prognosis and shortened survival time. Trastuzumab (Herceptin), a humanized antibody directed to the ErbB2 protein, and lapatinib (Tykerb), a small molecule ErbB tyrosine kinase inhibitor (TKI), are currently employed in the treatment of ErbB2-positive breast cancer patients. However, a significant proportion of ErbB2-positive tumors develop resistance to Herceptin, and emerging evidence suggests that tumors also develop resistance to TKIs. These observations validate the ErbB2 receptor as a target in the therapeutic intervention of breast cancer, but prompt questions as to whether more specific and efficient methods for interfering with ErbB signaling in breast tumors may be developed. However, an understanding of how extracellular ligand-induced dimerization invokes activating changes in the intracellular receptor kinase domains has been hindered owing to the current inability to obtain large quantities of full-length ErbB proteins, poor water solubility of the membrane protein, and the large size of each monomer unit.
To address these complications, I plan to synthesize the ErbB receptors into synthetic nanolipoprotein particles (NLPs). This process has been successfully demonstrated using active G protein-coupled receptors by our lab. I hypothesize that synthesis of ErbB receptors complexed with NLPs offers a powerful new approach to address key questions concerning their structure and activation, and will facilitate the discovery of novel therapeutics. The impact of the proposed studies will be to provide structural insight into ErbB receptor activation to ultimately facilitate the design of novel and more effective ErbB-directed therapeutic agents.