Curing cancer with bacteria

It was my turn to do journal club today, which is where we do a talk to our lab group about a science paper that has recently come out. Today's title was "Sequential treatment of drug-resistant tumors with targeted minicells containing siRNA or a cytotoxic drug", by MacDiarmid et al., and it was a strange, though interesting one. (Reference: Nature Biotech 27 643 - 651 (July 2009))

I've had a long standing interest in gene therapy, which is where you would use genetic factors to cure a condition, rather that just administering a drug. This paper focused on an alternative treatment for cancer. A lot of tumours become resistant to the drugs used for chemotherapy, which is often due to a mutation which leads to the cell making lots of a certain type of protein that prevents the drug taking action. Increasing the dosage may only make the patient sick due to side-effects of the drug, while the tumour survives.

MacDiarmid et al. used a combination of small interfering RNA, or siRNA, to reduce the resistance of a tumour cell to drugs, and a novel method of delivering the siRNA directly to the tumour, namely bacterially derived minicells. Minicells are basically bacterial cells lacking any insides that can be loaded up with genetic material or chemical compounds. They are formed from a mutant strain of bacteria that does not divide properly. Usually bacteria have a main chromosome, but minicells lack this and are very small as a result. They are really not much more than a sack surrounded by a lipid (fat) membrane. This can be loaded up with a drug for instance by incubating the minicells and the drug together. The minicell can be programmed to deliver its contents to a target cell by the use of a special antibody. The antibody recognises part of the minicell wall, and also an antigen presented by the target cell, which in this case is the EGF-receptor (EGF = epidermal growth factor) which is found in high concentrations on the outside of many types of cancer cell.

In this case, the target cell was a human tumour that had been grafted onto some unfortunate mice, and was expressing the drug resitance gene MDR1 (for multi-drug resistance). The Minicells get into the tumour cells and get eaten up by the cell, but release the siRNA payload. This activates the RNA silencing system to prevent expression of the MDR1 gene, and thus make the tumour drug-susceptible again. They then followed this up with another treatment, where the minicells were loaded with a drug which could then kill the tumour off.

As for the results, they treated mice bearing various types of tumour with the minicells carrying anti-MDR1 siRNA and then used minicells carrying a drug. The tumours regressed in size, and the mice survived, while the treated ones did not. The controls used were good - minicells which were not targeted to the tumour, ones which has a nonsense siRNA, which has basically a random sequence so does not affect any gene, and various combinations of minicells and standard drug administration. None of the control treatments had any effect.

So this strategy has a lot of potential in humans, assuming that people could accept a treatment involving what is basically the outside of a bacterial cell, and some genetic tinkering. I would imagine there would be a lot of problems with the human immune response as well. One thing the authors did not show was whether the treatment would work against a tumour of mouse origin, as they only used grafted human tumour cell-lines. Their strategy was to use an anitbody against EGF-r, which although it is expressed highly in tumours, is also expressed elsewhere in the cell. They used an antibody against the human EGF-r to target the minicells, which probably doesn't react very well with EGF-r of mouse origin; a good control would have been to use an antibody against mouse EGF-r. Also, although the treated mice survived, it wasn't clear whether the tumour had regressed or been killed off. I suppose if it extends your life by a few years, it still would make a good treatment, but there are obviously a lot more studies to be done.