Selective mitochondrial chemotherapy, decimates brain tumours and headed for human trials.

An experimental drug that attacks brain tumour tissue by crippling the cells’ energy source called the mitochondria has passed early tests in animal models and human tissue cultures, state researchers Houston Methodist and Weill Cornell Medical College.  The team designed a drug called MP-MUS that destroyed 90 to 95 percent 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.  The study is published in the journal ChemMedChem.

Previous studies from the lab have 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 to cancer cells selectively, leaving healthy brain cells alone. To the team’s knowledge, this is the first known example of selective mitochondrial chemotherapy, which they believe represents a powerful new approach to brain cancer.

Medical options for brain tumour patients are lacking explain the team.  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 9 to 15 months, and patients’ quality of life during that period isn’t very good.  For that reason the medical community 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 (a type of brain tumour) develop from brain cells called astrocytes. Gliomas account for as much as 20 to 30 percent 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.

The team state that 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. 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.

In the current study the team found that they could achieve profound effects with MP-MUS at very low concentrations, around 75 micromolar.  By contrast, temozolomide must be used at concentrations two to three times that to be of any use to patients.  The new approach is designed to capitalize 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.  The researchers hope that they are one step ahead of the cancer cells, as they 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.

The team have entered into an agreement with Virtici, LLC to develop MP-MUS and are currently preparing toxicology studies which are required prior to clinical trials.

Source:  Houston Methodist