Key driver for treatment of deadly brain cancer identified

Key driver for treatment of deadly brain cancer identified

Glioblastoma multiforme is a particularly deadly cancer. A person diagnosed with this type of brain tumor typically survives 15 months, if given the best care.

To study how glioblastoma multiforme spreads, the team focused on a transcription factor called nuclear factor kB (or NF-kB). A transcription factor is a protein that binds to DNA and controls the fate of gene expression for a particular set of genes. Several known factors can trigger NF-kB activity in a cell, including ultraviolet and ionizing radiation, immune proteins (cytokines) and DNA damage.

The team started with a mouse model of glioblastoma multiforme and used genetic tools to manipulate cells into shutting down NF-kB activity in two ways. The team ramped up the presence of a protein called IkBaM, which inhibits NF-kB activity. They also eliminated an enzyme that increases NF-kB activity. With less NF-kB activity, tumor growth slowed and mice lived significantly longer then mice whose NF-kB activity was left alone. But while these genetic experiments demonstrated the role of NF-kB in glioblastoma multiforme, they aren't a feasible treatment in humans.

Instead of using genetic tools, researchers sought to treat the brain tumors in a way that also changed the tumor microenvironment. The scientists fed mice a peptide (called NBD) that is known to block NF-kB activity when NF-kB is triggered by cytokines (proteins produced by the immune system). The NBD peptide easily travels across the central nervous system, and can successfully penetrate glioblastoma tumor cells. Treating mice with the NBD peptide doubled their typical survival time compared to mice that didn't get the NBD peptide.

Yet, while the NBD peptide kept the tumors at bay, the peptide treatment eventually causes toxicity, most likely in the liver. So researchers explored another tactic to slow NF-kB activity.

Curbing NF-kB activity can be tricky because NF-kB has many important roles: it helps regulate cell survival, inflammation and immunity among many other functions in the cell.

Salk scientists tracked which genes were influenced by NF-kB and found one, Timp1, which has been previously implicated in lung cancer. Targeting the Timp1 gene in treatment also slowed tumor growth and increased survival time in mice by a few months.