An axial or horizontal magnetic resonance image of a glioblastoma multiforme brain tumor in a human patient. Image courtesy of RadioGraphics.
Killing killer brain tumors
Glioblastoma multiforme are the most common and lethal of brain tumors in adults. The median survival time after diagnosis is just 12 to 14 months. The condition is almost invariably fatal.
Compounding their deadliness, GBMs tend to become quickly resistant to current drug treatments. In a paper published this week in the Proceedings of the National Academy of Sciences, researchers at the Ludwig Institute for Cancer Research at the University of California, San Diego say they may know why, describing a new molecular pathway that might eventually lead to more effective GBM therapies.
The study, headed Paul Mischel, MD, a professor in the department of pathology in UC San Diego’s School of Medicine, looked at a signaling pathway called the mammalian target of rapamycin or mTOR and at a multipurpose gene-encoded protein called promyleocytic leukemia or PML.
The work builds upon earlier research suggesting that the best way to kill GBM tumors is to block the signaling pathways that preserve and promote their survival.
MTOR is “hyperactivated” in close to 90 percent of glioblastomas and plays a critical role in regulating tumor growth and survival. It is considered to be a major therapeutic target. However, PML causes resistance to drugs designed to inhibit mTOR signaling. When glioblastoma patients are treated with mTOR-inhibitory drugs, PML levels rise and drug resistance grows, eventually rendering the drugs useless.
So the researchers went looking for something that suppresses or reduces PML levels, which would leave tumors more vulnerable to mTOR inhibitor drugs. They believe they’ve found it in arsenic trioxide, a molecule whose therapeutic use dates back to traditional Chinese medicine. In low doses, arsenic trioxide has been found to degrade the PML protein in leukemia patients. In their tests, the UC San Diego scientists discovered that it did the same in mice with brain tumors, reversing resistance to mTOR inhibitory drugs so that there was massive cancer cell death and significant tumor shrinkage, with no ill side effects.
Mischel and colleagues are now planning to test the therapy in people. You can read more about their research here.