Preclinical studies using lung cancer cells have demonstrated, for the first time, that mda-7 protein binds to a critical cellular enzyme called PKR. The binding of mda-7 to PKR is essential for the anti-cancer activity of INGN 241 and the identification of this binding partner demonstrates a significant advancement in understanding how this therapeutic can be effective against cancer.
Additional studies identified bystander killing of pancreatic cancer cells by mda-7 protein, meaning INGN 241 not only kills pancreatic cancer cells but also neighboring cells. Bystander killing works by the release of mda-7 from adjacent INGN 241 treated cells, thereby producing cell death through two independent mechanisms. The receptor on pancreatic tumor cells that mediates this killing was identified.
Previous lung cancer studies demonstrated that INGN 241 up-regulated a critical cellular enzyme, PKR, in lung cancer cells. PKR is an essential enzyme called a kinase that can alter the function of cell and virus proteins by adding chemicals called phosphate groups (in a process called phosphorylation).
In this study, administration of INGN 241 led to time and dose dependent induction of PKR which caused the lung cancer cells to die. Further studies demonstrated that mda-7 protein produced by INGN 241 physically interacts with PKR protein, and that both mda-7 and PKR are phosphorylated. The data suggests that mda-7 binding can alter the activity of PKR, resulting in apoptosis in lung cancer cells. This study identified the first known binding protein for mda-7 and indicates that phosphorylation of mda-7 is important for its activity.
A second study evaluated the anti-cancer mechanisms of action of mda-7 in pancreatic cancer cell lines. Data from this study show that treatment of pancreatic cancer cells with INGN 241 leads to rapid cell death via apoptosis, or programmed cell death. Furthermore, INGN 241-treated cells secrete mda-7 protein, which binds to the IL-20 receptor on neighboring pancreatic cancer cells and triggers apoptosis and cell death.
INGN 241 currently is being evaluated in a phase II trial in patients with malignant melanoma.