The recent availability of a portfolio of EGF receptor antagonists for anticancer treatment have been a major advance in cancer therapy. However, there is still much to be learned about the EGF signaling pathway, the variability of patient responses to these drugs, and optimal combination therapies. Dr. Gunawardena’s laboratory studies, which blend mathematical modeling with microfluidics and fluoresence microscopy, are paving the way for understanding at a fundamental level how the EGF signaling pathway responds dynamically to stimulation by ligands and to pharmacological intervention. This may help explain why cancer patients display different therapeutic benefit to EGF receptor antagonists (i.e., what key biochemical steps determines the therapeutic efficacy). In addition to laying the foundation for improved therapeutics, there will be a high likelihood that this research will convert empirical assessment of anti-EGF receptor drug therapy responses into a predictive model. A second area of potential interest to industry is the creation of a new formalized biological language that can assist in knowledge management and predictions, and company tools already in existence may facilitate further development in this area.

• Utilize single-cell biophysical technologies, microfluidics and fluorescence microscopy to determine how molecular networks respond dynamically to stimulation and pharmacological intervention.
• Explore pharmacological effects on the EGF signaling pathway and the cell-to-cell variability that may underlie differences in patient responses to drugs.
• Derive mathematical descriptions that can elucidate the myriad of circuitry connections that are functioning during the cellular response to an extracellular modulator such as EGF.
• Develop a formalized biological language for describing molecular networks in a way that can be interrogated and analyzed.

Dr. Gunawardena’s laboratory has applied a theoretical approach to the complex intracellular biochemical circuitry that registers dynamic parallel and sequential responses upon perturbations of transmembrane receptors by extracellular cues (e.g., growth factors and cytokines). Using the epidermal growth factor/MAP kinase signaling cascade as a model pathway, their approach has been to employ mathematical analysis and empirical laboratory studies to gain insights into the intricate protein regulation that receives, transmits, and converts biochemical signals into discrete morphological phenomena such as cell migration, division, etc. The experimental approach includes single-cell technology such as Fluorescence Correlation Spectroscopy for detecting protein-protein interactions and multi-layer microfluidic devices for generating complex temporal and spatial patterns of ligand stimulation. Mathematical analysis has been applied to the paradigm of multisite protein phosphorylation, leading to mathematical predictions about the underlying regulatory networks of kinases and phosphatases. A key idea introduced by the lab is the significance of the global phosphorylation state of a protein, in place of site-specific phosphorylation. These protein phosphorylation studies have been the subject of several recent articles published in prestigious journals.

Biological Mechanisms and Pathways

• EGF •
• MAP kinase •
• Multisite phosphorylation •
• Oncology •
• Phosphatase •
• Signal transduction •
• Systems Biology
•  

Cancer

• Cancer •
• EGF •
• MAP kinase •
• Oncology
•  

Disease Mechanisms

• Cancer
•  

Research Tools and Instrumentation

• Computational infrastructure/tools •
• Fluorescence correlation spectroscopy •
• Mathematical modeling
•  

Therapeutic Discovery Tools and Assays

• Cancer
•  

Therapeutics

• Erbitux •
• Iressa •
• Pharmacological agents •
• Tarceva
•