Salmonella Reprogrammed For One Mission: Seek and Destroy Cancer

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Great strides have been made in treating various forms of cancer, thus extending lives. But for people with Glioblastoma, a particular type of aggressive brain cancer, very little has worked. Recently, however, a lot of research has been done at the nanoscale, modifying evolution's 4 billion year progress to suit our own needs.

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A team of biomedical engineers, including Duke University Pratt School of Engineering's Dean, Dr. Ravi Bellamkonda, has published their most recent innovation in the  journal Molecular Therapy – Oncolytics.

This cancer is very invasive in the brain. It doesn't stay in one place. When a tumor doesn't have a boundary or a clear edge, then it becomes very challenging to remove it all. You leave some behind because the tumor is migrating and invading the rest of the brain.

The principle we're testing here is, how do you design a system where you have a therapy that goes everywhere, but is only toxic to the region that the tumor is in and not elsewhere?

Some current treatments involve forcing chemicals through the brain, in an attempt to engage all of the cancer cells. This is dicey because it also leaves healthy brain cells vulnerable to the treatment. Surgery is also of limited benefit.

Taking out one extra millimeter of brain could mean the difference between speech and no speech, between walking and not walking. And so, in an organ like the brain, it is particularly important to figure out a way not to kill the normal cells and kill a distributed tumor.

So how do you do this without harming the brain? The answer, in this case, comes in the form of a bacteria called Salmonella, which has been genetically modified so it won't make anyone sick.

Shawn's note, according to the CDC:
"Every year, Salmonella is estimated[PDF - 1 page] to cause one million foodborne illnesses in the United States, with 19,000 hospitalizations and 380 deaths. Most persons infected with Salmonella develop diarrhea, fever, and abdominal cramps 12 to 72 hours after infection. The illness usually lasts 4 to 7 days, and most persons recover without treatment. However, in some persons, the diarrhea may be so severe that the patient needs to be hospitalized."

The reason Salmonella was interesting to us is it has this property of being able to move in what we call extracellular space. If I put this bacteria in one corner of the brain on the surface, they have the ability to go everywhere in the brain, but they don't grow everywhere in the brain because we've engineered it such that it's hungry for certain essential compounds that we call purines.

So, by doing that, only in the tumor regions which are rich in purines, do they actually multiply and grow.

That's just the first step.

We can engineer it genetically to produce proteins that it does not normally produce. So we made Salmonella that made two proteins that work together really well to kill tumors. But we didn't want them to make these proteins everywhere in the brain. Tumor regions have low oxygen tension. So we use that feature to our advantage and engineered this bacteria such that it only triggers these proteins being made when there is low oxygen tension.

So, the team used Salmonella because it's mobile in the brain. They made it dependent on cancer-abundant purines. Then they programmed it to only produce cancer killing proteins in low oxygen areas, found only around brain tumors.

When the tumor is gone, the Salmonella dies off safely because it has essentially consumed all of its own food source.

Genius!

Using a lab rat model, this method has increased the survival rate by 20%.

We are now trying to understand why it is that, in 20% of the cases, we had complete cure, and in 80% of the cases, when we treated the rats in this case, we did not. It could be because in those cases for some reason, the bacteria that we injected were not as effective. Or it could be that there's variation within tumors, and the really aggressive ones outpace the good that these bacteria can do. We see evidence that, even in the cases of the animals that did not respond, initially they did, and then the tumor overtakes that response. So don't take me wrong. The 20% cure is amazing for a disease we did not move the needle at all on for so many years. We're very excited about that. But we're very interested in understanding how we can make that 40, 60, 80 percent of the cases... or 100% with some luck.