Gamitrinib is a chemical inhibitor first developed by Altieri and his colleagues in 2009 at the University of Massachusetts. The drug binds to and inhibits Hsp90Heat Shock Protein-90a so-called chaperone protein that is highly active in mitochondria and other cellular organelles where it helps regulate and "rescue" other proteins, particularly in times of stress. Their previous studies have shown that Gamitrinib is effective in damaging tumor cell mitochondria, which can lead to cell death.
"When tumor cells are confronted with lower concentrations of Gamitrinib, they mount a stress-related defensive system, essentially eating damaged mitochondria and altering how genes are turned on and off to compensate for induced defects in the mitochondria," Altieri said. "This process naturally suppresses Nuclear Factor-kappa Beta, a protein that prevents apoptosis from happening. Ironically, it's this very defensive measure that we can exploit in killing tumor cells."
Nuclear Factor-kappa Beta (NF-κΒ) broadly promotes survival in tumors by halting the processes that lead to apoptosis. Altieri and his colleagues wanted to see if the suppression of NF-κΒ would provide an opportunity for TRAIL, a small engineered molecule that mimics the signals used to induce apoptosis.
In their experiments, researchers confirmed previous studies that showed how TRAIL alone did not affect glioblastoma in cell and animal models of the disease. TRAIL plus Gamitrinib, however, stimulated damage to mitochondria in tumor cells, which started a cascading series of reactions, culminating in cell death. Preclinical experiments conducted in mouse models of glioblastoma demonstrated that the combination did not cause any detectable toxic side effects.
According to Altieri, the fact that Gamitrinib and TRAIL are in clinical development already may help
|Contact: Greg Lester|
The Wistar Institute