Glioblastoma multiforme is a rare but aggressive brain cancer, accounting for nearly half of all primary brain tumor cases in the United States. Typically, patients who receive no treatments succumb to the disease within three months of a diagnosis.
Only five percent of patients survive for more than three years and a staggering one in every 5,000 patients lives for more than a decade.
Aimed at improving medical treatments for the disease, a team of researchers led by Gregory Riggins from the School of Medicine conducted a study looking at novel drug treatments.
Upon doing an initial screen in vitro for compounds that slow the growth of the cancer cells, one drug emerged above the rest as a potential candidate for further study. This compound, called A-443654, acts by inhibiting a well-known pathway common to brain cancers.
The pathway involved the up-regulation of Akt, also known as protein kinase B. This protein acts by slowing down the rate of programmed cell death, called apoptosis, and also increases the rate of growth for cells. This protein pathway is ideal for cancers because it stops the cells from dying, and it increases their growth rate in the process.
By inhibiting this protein, the cancer cells should have reduced growth and increased apoptosis - exactly the results found by the researchers. Compared to normal cells, the glioblastoma multiforme cells had inhibited growth and increased rates of apoptosis.
Also, compared to other potential drug candidates and modified versions of the ideal drug, A-443654 performed the best, showcasing its ability as a potential therapeutic drug.
Not only does the drug work on glioblastoma multiforme, but it also inhibits growth in glioblastoma multiforme stem-like cells (GLSC), also known as cancer stem cells.
A current hypothesis in the cancer field is that some, if not most, cancers originate from a cancer stem cell capable of creating the entire tumor. These cancer stem cells have similar properties to normal stem cells in that they can self-renew and create the cells that constitute the tumor.
This hypothesis may also account for the resistance to certain therapies and if the cancer stem cell can be targeted, then there may be an increased chance for patient survival.
Repeating the experiments done on glioblastoma multiforme on the GLSCs, the researchers found these cells to be inhibited as well. Again, this drug now has increased potential for clinical use.
Finally, the team took the next step to see if A-443654 could increase the survival time of mice given the glioblastoma multiforme cancer. They administered the drug locally in the brain to mice and looked at the survival times.
Compared to the mice that received no drugs, the mice receiving treatments lived 43 to 79 percent longer. This work represents a step forward in the treatment of glioblastoma multiforme, and with time, the researchers hope to take this drug to the clinical setting to treat patients.
