Design of combination therapy for engineered bacterial therapeutics in non-small cell lung cancer
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 tre...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2022-12-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-26105-1 |
| _version_ | 1828164677112168448 |
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| author | Dhruba Deb Yangfan Wu Courtney Coker Tetsuhiro Harimoto Ruoqi Huang Tal Danino |
| author_facet | Dhruba Deb Yangfan Wu Courtney Coker Tetsuhiro Harimoto Ruoqi Huang Tal Danino |
| author_sort | Dhruba Deb |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T01:30:23Z |
| format | Article |
| id | doaj.art-1ea02c3efcf74f9cb07bea2d420aef0a |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-12T01:30:23Z |
| publishDate | 2022-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-1ea02c3efcf74f9cb07bea2d420aef0a2022-12-22T03:53:31ZengNature PortfolioScientific Reports2045-23222022-12-011211910.1038/s41598-022-26105-1Design of combination therapy for engineered bacterial therapeutics in non-small cell lung cancerDhruba Deb0Yangfan Wu1Courtney Coker2Tetsuhiro Harimoto3Ruoqi Huang4Tal Danino5Department of Biomedical Engineering, Columbia UniversityDepartment of Biomedical Engineering, Columbia UniversityDepartment of Biomedical Engineering, Columbia UniversityDepartment of Biomedical Engineering, Columbia UniversityDepartment of Biomedical Engineering, Columbia UniversityDepartment of Biomedical Engineering, Columbia UniversityAbstract 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.https://doi.org/10.1038/s41598-022-26105-1 |
| spellingShingle | Dhruba Deb Yangfan Wu Courtney Coker Tetsuhiro Harimoto Ruoqi Huang Tal Danino Design of combination therapy for engineered bacterial therapeutics in non-small cell lung cancer Scientific Reports |
| title | Design of combination therapy for engineered bacterial therapeutics in non-small cell lung cancer |
| title_full | Design of combination therapy for engineered bacterial therapeutics in non-small cell lung cancer |
| title_fullStr | Design of combination therapy for engineered bacterial therapeutics in non-small cell lung cancer |
| title_full_unstemmed | Design of combination therapy for engineered bacterial therapeutics in non-small cell lung cancer |
| title_short | Design of combination therapy for engineered bacterial therapeutics in non-small cell lung cancer |
| title_sort | design of combination therapy for engineered bacterial therapeutics in non small cell lung cancer |
| url | https://doi.org/10.1038/s41598-022-26105-1 |
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