Researchers from Houston Methodist Hospital have developed a so-called mitochondrial smart bomb that can be used to treat brain tumors by attacking the cell’s energy source, according to a new study appearing in the April edition of the journal ChemMedChem.
In the study, Dr. David S. Baskin, director of the Houston Methodist Kenneth R. Peak Brain & Pituitary Tumor Center, Dr. Martyn Sharpe, Peak Center Head of Research, and their colleagues describe how an experimental drug treated brain tumor tissue by targeting mitochondria in early laboratory tests involving animal models and human tissue cultures.
The drug, MP-MUS, was designed by Drs. Baskin and Sharpe and destroyed between 90 and 95 percent of malignant glioma cells (a type of tumor that starts in the brain or spine and arises from glial cells) without appearing to have any adverse affect on healthy human brain cells.
Selective mitochondrial chemotherapy
The finding compliments soon-to-be published research showing that the same drug can be used to treat brain cancer grown in the brains of mice. They hope that they will be able to begin testing the drug in human clinical trials in the near future, possibly in 2016.
“We are very optimistic that we’ll get there,” Dr. Baskin said. “Our past work has shown that MP-MUS has very low toxicity until it gets into tumor cells. Once it arrives, it is changed to its active form, doing a lot of damage where we want it to, leaving healthy brain cells alone – a bit like a ‘smart bomb.’ To our knowledge, this is the first known example of selective mitochondrial chemotherapy, which we believe represents a powerful new approach to brain cancer.”
“Because of where the tumors are located, and because of the way they can infiltrate healthy tissue, surgery is often not helpful long term. The most effective chemotherapy drug available right now, temozolomide, only extends life from 9 to 15 months, and patients’ quality of life during that period isn’t very good.”
How does it work?
Dr. Baskin and Dr. Sharpe have been searching for some way to treat gliomas, which account for up to 30 percent of all tumors of the brain and central nervous system. One of the areas they have focused on is treating the cancer by targeting the mitochondrial that provide tumor cells with energy.
In cancer cells, they explain, part of this feature is deactivated, causing cells to rely upon other system that generate energy – but even so, tumor cells cannot grow and divide unless these pill-shaped powerhouses are healthy. By targeting an enzyme (MAO-B) that is over-expressed in brain tumor cells, MP-MUS reduces the negative impact on healthy cells while the drug becomes trapped inside tumor cells, where it attacks the mitochondrial DNA.
“We found that we could achieve profound effects with MP-MUS at very low concentrations, around 75 micromolar,” said Dr. Baskin. “By contrast, temozolomide must be used at concentrations two to three times that to be of any use to patients. Our approach is designed to capitalize on what is going inside the cells. Tumor cells have much more MAO-B, and when challenged, make even more MAO-B as a sort of defensive response. We hope that we are one step ahead of the cancer cells, as we are using that very fact to kill them.”
The study authors reported that the toxicity of the drug to healthy cells remained low even when administered at concentrations of up to 180 micromolar. This information will help scientists as they evaluate safety and efficacy trials in human patients. The Houston Methodist team has already signed a deal with Virtici, LLC to develop MP-MUS, and is currently in the process of preparing toxicology studies, which are required prior to clinical trials.