Experimental Analysis and Computational Modeling of Network States and Drug Responses in the PI3K/Akt/mTOR Network
Abstract
Therapeutic targeting of the PI3K/Akt/mTOR pathway is expected to be highly effective against breast cancer, and numerous clinical trials are underway for compounds targeting pathway components. However, current research is revealing that the connectivity and dynamical behavior of this network is highly complex, due to numerous feedback loops and crosstalk connections. The goal of this research project is to develop quantitative models of the PI3K network that will enable the effects of inhibitors to be predicted across different types of cell lines and tumors. We have now constructed and are validating two different quantitative models of signaling in the PI3K network. The first, a mechanistic rule-based model, recapitulates the molecular steps involved in the membrane recruitment and phosphorylation of Akt. In developing this model, we have constructed a number of new experimental tools, and these have revealed a novel positive feedback loop controlling phosphorylation at Ser473, a key step in Akt activation. The second model is a data-driven model that is based on high throughput imaging and high-content quantitation of individual cells responding to growth factors and signaling pathway inhibitors. This model seeks to link the signaling states of individual cells to the behavior of the population, and has revealed quantitative differences between normal and oncogene-driven cell proliferation in the efficiency of PI3K/Akt/mTOR signaling.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2009
- Accession Number
- ADA514757
Entities
People
- John G Albeck
Organizations
- Harvard University