Caption: The new drug MP-MUS (yellow) attacks cancer cell mitochondria by infiltrating both inner and outer membranes (green) after being converted from an inactive, non-toxic form to an active, toxic form by the enzyme MAO-B (purple). Once inside, the drug damages mitochondrial DNA, which cannot be repaired.
As reported in April 2015 ChemMedChem (early online), Houston Methodist Kenneth R Peak Brain & Pituitary Tumor Center director David S Baskin and Peak Center Head of Research Martyn Sharpe, designed a drug called MP-MUS that destroyed 90 to 95% of malignant glioma cells, yet in other experiments did not seem to adversely affect healthy human brain cells (in vitro). This compliments a soon to be published extensive study showing the same drug can treat human brain cancer grown in the brains of mice. Researchers hope to begin testing the drug in human clinical trials in 2016 or 2017.
“We are very optimistic that we will get there,” says Baskin, also vice chair of the Department of Neurosurgery at Houston Methodist Hospital. “Our past work has shown that MP-MUS has very low toxicity until it gets into tumour 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.”
Medical options for brain tumour patients are woeful, Baskin says. “It is a horrible diagnosis. Because of where the tumours 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 nine to 15 months, and patients’ quality of life during that period is not very good.”
For that reason, Baskin says he and researchers around the world have been looking for new treatment approaches, such as vaccines intended to aid the body’s immune system’s recognition and removal of tumour cells, gene therapy and, in the present case, targeting tumour cell mitochondria.
Gliomas develop from brain cells called astrocytes. Gliomas account for as much as 20 to 30% of all tumours of the brain and central nervous system.
Mitochondria are often referred to as the “powerhouses” of cells—including misbehaving cancer cells—because they help cells create energy. In cancer cells this feature is partially switched off, causing cells to rely on other systems that generate energy. The numerous pill-shaped mitochondria in each cell perform a number of other crucial functions, however, and even cancer cells cannot grow and divide without healthy mitochondria.
As luck would have it, an enzyme called MAO-B is over-expressed in brain tumour cells, which is the target of MP-MUS. This means that healthy cells are only exposed to low levels of MP-MUS and their mitochondria to very low levels of P+-MUS, Baskin says. On the other hand, in tumour cells the vast majority of the pro-drug is converted into P+-MUS, which essentially traps the drug inside their mitochondria where it attacks the mitochondrial DNA.
“We found that we could achieve profound effects with MP-MUS at very low concentrations, around 75 micromolar,” says Baskin, professor of Neurological Surgery, Weill Cornell Medical College. “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 capitalise on what is going inside the cells. Tumour 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 researchers reported MP-MUS’s toxicity to healthy cells remained low at concentrations as high as 180 micromolar. This information will be useful to the researchers as they consider safety and efficacy trials in human patients.
Houston Methodist and Baskin and Sharpe entered into an agreement with Virtici, LLC to develop MP-MUS and are currently preparing toxicology studies which are required prior to clinical trials.
While human clinical trials have not yet begun for MP-MUS, Houston Methodist Neurological Institute doctors are overseeing participation in a number of clinical trials related to gliomas and glioblastomas.