Lung cancer is the second most common type of cancer and is responsible for the most cancer-related death in the U.S. The American Cancer Society reports that more than 235,000 people were diagnosed with lung cancer in 2021. There are three major types of lung cancer: non-small cell lung cancer (85% of cases), small cell lung cancer (10% of cases), and lung carcinoid tumor (5% of cases). The causes of lung cancer include but are not limited to smoking, secondhand smoke, exposure to certain toxins, and family history. The symptoms include cough with blood, chest pain, wheezing, and weight loss when the cancer is in the advanced stage. Depending on the type of lung cancer and what stage it has progressed to, the treatment will be different. Broadly the treatment involves surgical resection, radiation, chemotherapy, targeted therapy and immunotherapy. However, to treat this complex disease researchers are always looking for new and improved treatment modalities.
A research group at Columbia Engineering led by Dr. Dhruba Deb in the lab of professor Tal Danino developed a new therapeutic to treat non-small cell lung cancer (NSCLC) by combining an engineered bacteria with targeted therapy to enhance the treatment efficacy without any additional toxicity in laboratory animal models. This finding was published in Scientific Report on December 13, 2022.
By engineering a toxin named theta (θ) toxin in the bacteria S.typhimurium and by testing the response of a variety of NSCLC cells to this engineered bacteria, the research group found that θ toxin can kill a variety of NSCLC cells even with different genetic background such as mutated growth factor receptor like KRAS or EGFR, the most common mutations found in NSCLC. The research group also administered locally live S.typhimurium expressing theta toxin (Stθ) in NSCLC tumor cells in the mouse model and found a 2.5-fold reduction of tumor growth within a week compared to the control group.
With the success of testing live S.typhimurium expressing theta toxin (Stθ) in mouse model and no toxicity found in the peripheral organs, the research group tested whether using the engineered bacteria could enhance the efficacy of the standard of care chemotherapies as well as small molecular inhibitors. To identify potential drugs to combine with Stθ, the authors used RNA-sequencing. This helped to pinpoint which biochemical pathways in NSCLC cells were helping the cells to survive the Stθ treatment. To overcome this ability of NSCLC cells, the researchers blocked those biochemical pathways with drugs and eliminated the NSCLC cells. For example, one of the drugs, MK2206 when paired with Stθ treatment, blocks the NSCLC cells’ ability to survive via biochemical signaling of phosphorylated AKT that promotes survival and growth in response to extracellular signals. Key proteins involved are PI3K (phosphatidylinositol 3-kinase) and Akt (protein kinase B).. The research group also tested the combination treatment of MK2206 and Stθ in a mouse model. They found that the combination treatment of Stθ bacteria and MK2206 suppressed the tumor growth efficiently compared to treatment with only Stθ or only MK2206. Moreover, with lower dose of bacteria and drug use, they could observe similar treatment results and could possibly avoid the activation of the immune system caused by high dose of bacteria treatment. Taken together, this combination treatment is a potential therapeutic for the NSCLC.
There are several limitations in this study that need to be addressed before entering the clinical trial. First, the authors used a small number of animals per cohort in the in vivo study, so they plan to expand their study to assess the overall survival upon treatment. Second, the toxins themselves are not selectively targeted to the cancer cells, so they need to develop a selective delivery method to avoid the systemic toxicity. In the laboratory animal models, the local administration of the live bacteria acted as a selective delivery. But, further studies are necessary to use this live bacteria in human clinical trials. Overall, this study opens up new treatment options for patients diagnosed with the NSCLC.
Reviewed by: Sam Rossano, Margarita T. Angelova