Researchers combined bacterial toxins with drugs to treat lung cancer

Bacterial therapy has come into prominence as a new method to treat cancer lately. However, even though this therapeutic modality has swiftly advanced from laboratory studies to clinical trials in the previous five years, the most successful treatment for some forms of cancer may be in combination with other medications.

Minimizing any additional toxicity

The study combined bacterial medicines with other therapy techniques to increase therapeutic effectiveness while minimizing any side effects.

“We envision a fast and selective expansion of our pipeline to improve treatment efficacy and safety for solid tumors,” said Dhruba Deb, the first author of the study and an associate research scientist who studies the effect of bacterial toxins on lung cancer in Professor Tal Danino’s lab in Biomedical Engineering.

“As someone who has lost loved ones to cancer, I would like to see this strategy move from the bench to bedside in the future.”

Making use of RNA sequencing

The researchers employed RNA sequencing to determine how cancer cells respond to bacteria at the cellular and molecular levels. They first developed a theory hypothesis on which molecular pathways in cancer cells contributed to the cells’ resistance to bacterium treatment, and then to test it, they used current cancer medications to block these pathways.

The results eventually demonstrated that combining the drugs with bacterial toxins is more successful in killing lung cancer cells. As an example, in mouse models of lung cancer, they validated the combination of bacteria therapy with an AKT inhibitor.

“This new study describes an exciting drug development pipeline that has been previously unexplored in lung cancer – the use of toxins derived from bacteria,” said Upal Basu Roy, executive director of research, LUNGevity Foundation, USA.

“The preclinical data presented in the manuscript provides a strong rationale for continued research in this area, thereby opening up the possibility of new treatment options for patients diagnosed with this lethal disease.”

The next step for the scientists is to expand their research to larger-scale studies in preclinical models of difficult-to-treat lung cancers and work hand-in-hand with clinicians to reinforce its transition to clinical studies.

The study was published in Scientific Reports on December 13, 2022.

Abstract:

Synthetic biology enables the engineering of bacteria to safely deliver potent payloads to tumors for effective anti-cancer therapies. However, a central challenge for translation is determining ideal bacterial therapy candidates for specific cancers and integrating them with other drug treatment strategies to maximize efficacy. To address this, we designed a screening and evaluation pipeline for characterization of bacterial therapies in lung cancer models. We screened 10 engineered bacterial toxins across 6 non-small cell lung cancer patient-derived cell lines and identified theta toxin as a promising therapeutic candidate. Using a bacteria-spheroid co-culture system (BSCC), analysis of differentially expressed transcripts and gene set enrichment revealed significant changes in at least 10 signaling pathways with bacteria-producing theta toxin. We assessed combinatorial treatment of small molecule pharmaceutical inhibitors targeting 5 signaling molecules and of 2 chemotherapy drugs along with bacterially-produced theta toxin and showed improved dose-dependent response. This combination strategy was further tested and confirmed, with AKT signaling as an example, in a mouse model of lung cancer. In summary, we developed a pipeline to rapidly characterize bacterial therapies and integrate them with current targeted therapies for lung cancer.