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New Engineering Research Arms Bacteria to Kill Cancer Cells, Destroy Their Tumors, and Prevent Metastasis

Neil Forbes

Neil Forbes of the Chemical Engineering Department at the University of Massachusetts Amherst has received a five-year, $1.56-million grant from the National Institutes of Health (NIH) to engineer what he calls “super-safe Salmonella bacteria” to act as Trojan Horses and deliver cancer-killing agents directly into tumors. His Salmonella vectors – armed with special cancer-ravaging peptides and a gene-disrupting ribonucleic acid (RNA) called shRNA – are designed to steal into cancer tumors, interrupt essential cell processes there, destroy cancer cells, eliminate cancer stems cells, reduce tumor volume, and block the formation of metastases.

For more than 12 years, Forbes has been working on non-pathogenic Salmonella bacteria that can use their own self-propulsion system to venture deep into tumors and deliver cancer-destroying agents, all without causing the vicious side effects of many chemotherapy treatments.

The NIH project is the climax of that research. “The whole idea here is to make therapies both to prevent the spread of cancer tumors and treat the spread of cancer tumors,” explains Forbes. The NIH awarded the grant to Forbes and his collaborators, postdoctoral researcher Dr. Nele Van Dessel, as well as Aleyde Van Eynde and Mathieu Bollen, Cellular and Molecular Medicine, KU Leuven, Belgium.

As Forbes explains, the trick is that Salmonella travel directly and exclusively to cancer tumors.

“It sounds like science fiction, doesn’t it?” says Forbes. “But Salmonella bacteria, in effect, are each little robots that can swim wherever they want. They have propellers in the form of flagella, they have sensors so they can tell where they’re going, and they’re also little chemical factories. So what we’re doing as engineers is controlling where they go, what chemical we want them to make, and when they make it.”

The NIH project has several momentous aims, one of which is already a fait accompli: the Salmonella bacterial delivery system already perfected by Forbes. The other aims have to do with using the Salmonella to deliver cancer-killing and -disrupting peptides and RNAs that attack key regulatory proteins in the complex process by which cancer thrives and spreads. In addition, Forbes’ research will also suppress the expression of functioning cancer cells. 

The two proteins targeted by Forbes in the cancer cells, chromatin modifier EZH2 and its regulator NIPP1, control many of the processes that make cancer invasive and malignant. EZH2 is a key regulator of stem cell potency and differentiation. Depleting EZH2 impairs tumor proliferation and decreases tumor volume. Inhibiting EZH2 induces cancer stem cell differentiation and death. NIPP1 is an essential protein in development and proliferation. Among other consequences, depleting NIPP1 inhibits tumor growth.

Forbes’ specially modified Salmonella carry certain cancer-disrupting peptides that target EZH2 and its NIPP1 in tumors. The elegantly designed Salmonella also carry shRNA, implicated in various biological roles involving the coding, decoding, regulation, and expression of genes. shRNA possesses a sequence of RNA which makes a tight hairpin turn that can be used to silence target gene expression.

In this case, Forbes’ working hypothesis is that shRNA will suppress the expression of two specific cancer genes, which in turn will prevent the formation of stem cells that otherwise would cause the spread of cancer and the formation of new tumors.

This NIH project gives biomedicine the first viable method that targets EZH2 or NIPP1. Before this research, systemic therapy targeting these critical proteins was never feasible because it would have created unhealthy side-effects in patients, such as deregulating differentiation in regenerating tissue like skin and intestines. But the Salmonella bacteria engineered by Forbes can overcome this crucial problem by precisely delivering shRNAs and peptides into cancer cells, while sparing normal cells.

That’s one of the beauties of the Salmonella vector developed by Forbes: The cancer therapies he uses avoid the devastating side effects of many cancer treatments. As a 2008 article in the Wall Street Journal noted shortly after Forbes received a million-dollar grant from the National Cancer Institute, “His work, and others like it, highlights the intense search for treatments that target cancer cells without causing debilitating side effects such as weight and hair loss, excessive bleeding, and fatigue that are common with radiation and chemotherapy.”

“Our system targets only tumors and almost completely cuts out the bad side effects in patients,” says Forbes. “It concentrates in the places where you want it. So our system potentially cuts down on morbidity, or bad side effects, at the same time as it boosts survival rates.”

Forbes summarizes his groundbreaking project this way: “This research will establish a new therapeutic platform for controlled gene and protein delivery into cancer cells. Transient delivery of genes and proteins with bacteria will enable direct targeting of proteins and functions specifically in cancer cells. This study will create an epigenetic therapy with the potential to eradicate metastases and prevent their formation, two urgent clinical problems.” (November 2014)

 
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