In collaboration with Meenhard Herlyn, D.V.M., D.Sc., at the Wistar Institute, the Marmorstein group then tested the effectiveness of the agent using melanoma cell cultures. Melanoma was used as a model system for the study because the signaling pathway regulated by PI3K is highly mutated in melanoma, Marmorstein says.
In addition to PI3K, the PI3K signaling pathway includes another kinase called AKT, and a phosphatase, PTEN, which serves as a tumor suppressor.
What you will often find is that one of those three proteins, and sometimes others, are mutated in cancer, Marmorstein says.
Studies with human melanoma cells showed that E5 blocked AKT activity, thereby inhibiting the growth of cells. Further studies in 3D cultures of melanoma cells showed the agent also prevented melanoma cell invasion.
What weve shown is that our inhibitor can find the kinase that its designed to inhibit without inhibiting other kinases, which could produce unwanted side effects, he says.
Marmorstein says the group plans to improve upon the E5 compound by creating organometallic inhibitors that target other isoforms, or types, of PI3K. The PI3K family of kinases includes four types: alpha, beta, delta and gamma. Each type is associated with particular biological pathways and performs various functions in the cell.
Though some of the PI3K types are associated with cancer, others are not. The trick to building inhibitors with low side effects and toxicity is to create inhibitors that knock out the troublesome isoforms without disrupting the other types, Marmorstein says
|Contact: Abbey J. Porter|
The Wistar Institute