Research conducted by Duke University biomedical Engineers finds that an avirulent strain of Salmonella typhimurium may be able to deliver life-saving treatments directly to the cells in glioblastoma tumors.
When you hear the word Salmonella, you probably think about food poisoning rather than fighting brain cancer. However, one strain of the notorious bacterium may be able to do both.
A team of biomedical engineers currently based at Duke University recently announced that they believe an avirulent strain of Salmonella typhimurium could actually deliver life-saving treatments directly to the cells in glioblastoma (GBM) tumors, which are located in the supportive tissues of the brain and sometimes the spinal cord and are notoriously difficult to reach with treatment. “A comprehensive analysis of data from 10 years has indicated that only 0.7% (median) of administered dose of nanoparticles reach solid tumors,” noted Ravi Bellamkonda, PhD, Vinik Dean of the Pratt School of Engineering at Duke University and a professor of biomedical engineering, in the published research, which appeared in Molecular Therapy — Oncolytics.
Before the researchers loaded the bacterium with tumor-suppressing proteins and a cancer-cell-killing drug called Azurin, they tested their strain of S. typhimurium aggressively to make sure that it would not make the “patients” in the study, in this instance rats with human glioblastoma cells in their brains, sick. Moving forward, this will be particularly important since other strains of S. typhimurium have, in the past, made some pretty nasty headlines, including a 2008-2009 peanut-butter-linked outbreak that lead to the infection of 714 people in 46 states and Canada, according to the Centers for Disease Control and Prevention (CDC).
This case not only made headlines for months, but it was eventually covered in the New England Journal of Medicine because the original source of the contamination was not easy to identify. According to the study, "This nationwide outbreak of human Salmonella Typhimurium infections was linked to the eating of contaminated peanut butter, peanut paste, and roasted peanuts produced at the PCA facilities in Georgia and Texas… The ultimate cause of contamination in this outbreak is unknown; at the Georgia PCA facility, rainwater leakage into storage areas, storage of raw peanuts near roasted peanuts, and possibly inadequate peanut roaster temperatures suggest that salmonella may have arrived on raw peanuts or was introduced in the facility and survived processing. Since peanuts and peanut products were transferred between the Texas and Georgia facilities, both of which had inadequacies on inspection, it is not possible to say where the contamination originated."
“Our bacterial carrier has a mutation in the msbB gene that…impedes systemic toxicity,” Dr. Bellamkonda, adding that not only has the strain been used successfully in mouse studies, but that it has also been used in clinical trials with human patients with another form of cancer. Unfortunately, those trials did indicate that the bacterial strain alone without its load of cancer-fighting compounds cannot cause tumor cells to start killing themselves; that clinical trial is what led to this study, in which the S. typhimurium was bioengineered to express a protein that creates an “apoptotic” effect in tumors, meaning that it causes tumor cells, specifically, to, essentially, commit suicide. While instigating apoptosis is not a new method of attacking GBM tumors, past suboptimal methods of delivery have previously minimized the effectiveness of the strategy. “Absence of an efficient delivery system into solid tumors has dwarfed the effectiveness of these therapies,” Dr. Bellamkonda said. In this specific study, in addition to having a tumor-specific, apoptotic gene, the Salmonella bacterium was also designed to express a protein called Azurin, which has proven effective in inciting cancer-cell suicide, but is not able to penetrate GBM cells on its own.
When Dr. Bellamkonda and his team injected test animals with the engineered bacterium, test subjects had a survival rate of 19% compared with no survival of untreated test subjects. Although the span of time between the median survival span of the control group (26 human days) and the test group (29 days) may seem fairly short, half of the rats who received the treatment showed evidence of tumor suppression. Furthermore, according to research published in the International Journal of Preventative Medicine, one “rat day” translates to roughly 35 human days, meaning that a mere additional three 24-hour spans in a rat life could be equivalent to more than three months in human life extension, if not more. This indicates a clear potential for extending lifespan and allowing for other treatment options to have time to work as well. The researchers also noted that treated rats did not show any signs of illness: essentially, they did not have food poisoning as a result of the salmonella treatment.
The scientists concluded that the S. typhimurium strain designed to deliver the combination therapy from the modified gene and Azurin is an “advantageous” model when treating GBM because “drug diffusion is a major impediment to successful treatment” of this condition. Because S. typhimurium are motile, they can specifically target GBM on location and optimize drug delivery. The researchers’ next step will be to program the bacterium to produce even stronger drugs that will produce more significant reactions in the targeted tumors.