Posted May 30, 2024

Tal Danino, Ph.D., Columbia University

Tal Danino, Ph.D., Columbia University
(Photo by Diane Bondareff, Columbia Magazine)

Researchers continue to investigate probiotic bacteria as a potential therapeutic strategy for various cancers, including breast cancer. This is an approach that leverages the bacteria's natural ability to sense, interact with, and respond to their environment. Additionally, probiotic bacteria can be engineered to deliver antitumor agents to tumors, a preferred growth environment for probiotic bacteria, allowing for targeted therapeutic delivery. Despite the potential advantages of using bacteria-based cancer therapy, the toxicity of bacteria limits the effectiveness and tolerated dose of the therapy.¹ The ability of bacteria to multiply and deliver therapeutics to cancer tissues also requires precise control of the way they are handled by the body. Therefore, addressing the issue of systemic toxicity while enhancing therapeutic delivery presents a challenge for the potential use of bacteria in breast cancer therapy.

With support from an FY 2016 Breast Cancer Research Program Era of Hope Scholar Award, Tal Danino, Ph.D., and his team developed genetically manipulated bacteria to enable programmable expression of surface molecules that protect microbes, called capsular polysaccharides, or CAP, allowing the bacteria to avoid immune attack, thereby enhancing their colonization and drug delivery in tumors, while improving patient safety.

Through a FY 2016 Breast Cancer Research Program Era of Hope Scholar Award, Tal Danino, Ph.D., far left, and members of the Danino Lab at Columbia University developed genetically manipulated bacteria to enable programmable expression of surface molecules that protect microbes, called capsular polysaccharides, or CAP, allowing the bacteria to avoid immune attack, thereby enhancing their colonization and drug delivery in tumors, while improving patient safety. (Photo by Jane Nisselson, Columbia University School of Engineering, Director of Multimedia Communications)

As described in Nature Biotechnology, Danino and his research team studied the surface molecule CAP in the probiotic Escherichia coli strain Nissle 1917, or EcN. The team identified key genes involved in the production and regulation of CAP expression in response to interactions with environmental factors. They then created a novel inducible CAP system. Bacteria carrying the team's CAP system are referred to as EcN iCAP. After establishing programmability and control of CAP expression, the researchers conducted cell-culture studies and demonstrated the iCAP system can enhance bacterial survival in blood by providing protection from the immune system.

In mice, researchers found that the maximum tolerated dose of transiently induced EcN iCAP was about ten times higher than the wild type EcN or CAP knockout strain. Furthermore, when the research team tested bacteria engineered to produce an antitumor agent in a mouse model, the toxin-producing EcN iCAP suppressed tumor growth. Finally, the researchers used mouse models to demonstrate CAP activation after EcN iCAP is injected within a tumor with subsequent trafficking of the bacteria to tumors not injected with EcN iCAP. This finding suggests the potential utility of the EcN iCAP system as an alternate route of bacterial delivery to inaccessible tumors.

Danino's novel study demonstrated programmable surface expression of CAP in engineered bacteria to increase the maximum tolerated dose and enhance antitumor effects in mice. His team also identified several other potential genes involved in bacterial sensitivity to environmental factors, which may be investigated in future studies. Further investigation may accelerate the translation of engineered bacterial-based therapies into the clinic for the treatment of breast cancer.