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Projects / Programmes source: ARIS

Targeting, imaging and treating of colorectal cancer with safe theranostic bacteria

Research activity

Code Science Field Subfield
4.06.00  Biotechnical sciences  Biotechnology   

Code Science Field
T490  Technological sciences  Biotechnology 

Code Science Field
3.04  Medical and Health Sciences  Medical biotechnology 
Keywords
colorectal cancer, lactic acid bacteria, Lactococcus lactis, theranostic, protein delivery, targeted therapy, genetic engineering, CRISPR
Evaluation (rules)
source: COBISS
Researchers (11)
no. Code Name and surname Research area Role Period No. of publicationsNo. of publications
1.  24257  PhD Aleš Berlec  Pharmacy  Head  2018 - 2021  217 
2.  55064  Lara Bolčina  Pharmacy  Researcher  2020 - 2021  12 
3.  53738  PhD Krištof Bozovičar  Pharmacy  Researcher  2020  30 
4.  04648  PhD Janko Kos  Biotechnical sciences  Researcher  2018 - 2021  1,154 
5.  32431  PhD Peter Molek  Pharmacy  Researcher  2018 - 2019  52 
6.  32035  PhD Anja Pišlar  Biotechnology  Researcher  2020 - 2021  162 
7.  15600  Maja Šimaga    Technical associate  2018 - 2021 
8.  36337  PhD Katja Škrlec  Chemistry  Junior researcher  2018  30 
9.  07849  PhD Borut Štrukelj  Biochemistry and molecular biology  Researcher  2018 - 2021  1,123 
10.  34511  PhD Petra Zadravec  Pharmacy  Researcher  2019  26 
11.  52419  PhD Abida Zahirović  Biotechnology  Researcher  2018 - 2021  36 
Organisations (2)
no. Code Research organisation City Registration number No. of publicationsNo. of publications
1.  0106  Jožef Stefan Institute  Ljubljana  5051606000  90,063 
2.  0787  University of Ljubljana, Faculty of Pharmacy  Ljubljana  1626973  17,535 
Abstract
The aim of the proposed project is to develop safe theranostic lactic acid bacteria (ProbioTheranostics) that will be engineered with the ability to specifically target colorectal cancer cells, localize the tumor position using fluorescence imaging, and treat the colorectal cancer by exerting anti-inflammatory activity and modulating the composition of microbiota. ProbioTheranostics will be administered locally via oral route and will be tested in cell and animal colorectal cancer models. Colorectal cancer is the third most common cancer in the world with 1.2 million cases reported every year and increasing incidence. It therefore represents a heavy burden for the health system. Current treatment approaches (chemotherapy, surgery and monoclonal antibodies) have limited efficiency and severe side effects; researchers are therefore constantly looking for better treatment options. New approaches focus on the reduction of side effects, targeted therapy, combination therapy and concomitant therapy and diagnostics (theranostics). Immune system and intestinal microbiota are important factors in colorectal cancer. Immune cells play a role in tumor prevention, as well as in the progression of tumor development. A change in the composition of microbiota (dysbiosis) is a characteristic of colorectal cancer and contributes to its progression. Supplementation with probiotics from the group of lactic acid bacteria can influence the immune system and modulate microbiota composition. Apart from using wild-type beneficial probiotic bacteria they can also be genetically engineered to express recombinant proteins that provide additional therapeutic benefit. This approach was successfully demonstrated in the treatment of inflammatory bowel disease and, to a limited extent, in the treatment of colorectal cancer. Our research group has significant experience with genetic engineering of lactic acid bacteria and their testing in animal models that will serve as a foundation for the proposed project. We have prepared recombinant L. lactis with TNFα neutralizing ability. We have developed a new approach to coat unmodified lactic acid bacteria with protein binders. Additionally, we have demonstrated the expression of infrared fluorescent protein in lactic acid bacteria and thereby enabled in vivo imaging and tracking. In the proposed project we intend to develop supporting genetic engineering techniques for lactic acid bacteria that will enable inducible expression of multiple proteins and genome integration using CRISPR-Cas technique. Lactic acid bacteria will be used to express proteins for targeting of cancer surface antigens, protein that enables in vivo imaging, and proteins that will provide therapeutic benefit by neutralizing pro-inflammatory cytokines. Multiple protein moieties will be combined in a single bacterial species by multiple protein expression and heterologous protein coating. This will result in the engineering of theranostic bacterial species that will combine targeting, imaging and therapeutic properties. Additional engineering will be performed to establish regulatory acceptance and stability of theranostic bacteria. We will test the developed bacteria in cell line models in collaboration with Prof. Janko Kos from the Faculty of Pharmacy, who is an expert in cancer biology. Additionally, we will test the in vivo therapeutic efficacy and imaging-based diagnostics in a mouse model with chemically-induced colorectal cancer. The intrinsic efficacy of modified and unmodified probiotic bacteria on microbiota modulation will be evaluated with next generation sequencing. Our proposal represents a completely new concept for the use of safe engineered bacteria that could lead to the discovery of novel adjuvant therapeutic and diagnostic method for colorectal cancer. The complementary combination of experienced scientists and realistic project schedule speak in favor of the feasibility of the project.
Significance for science
The proposed project will, in the long run, contribute to the progress of oncology as it introduces completely new concept to treatment and diagnostics of colorectal cancer. The suggested probiotic theranostic bacteria (ProbioTheranostics) will be safe and presumably with little side effects; they could therefore be used as an alternative or adjuvant drug in cancer medicine. The proposed concept of ProbioTheranostics could trigger similar line of research in other fields of medicine in which microbiota plays an important role. We believe the project will lay the foundation for further research work in the field of targeted microbiota manipulation that is beginning to rapidly attract attention of pharmaceutical industry. The establishment of a new approach to bacterial engineering and functionalization will be important in the field of applied microbiology. The approach can be transferred to other microbial species or can be used for non-medicinal applications of lactic acid bacteria, e.g. biocatalysis. The project will contribute to the development of biotechnology, particularly to the biotechnology of lactic acid bacteria, as it will introduce new genetic engineering techniques, such as CRISPR-Cas mediated genome engineering and inducible double-protein expression system. The proposed project will contribute to the scientific development at the Department of Biotechnology at Jozef Stefan Institute. The project will upgrade the existing research and will create a starting point for further research, focusing on combinatorial treatment and clinical studies. The project will also contribute to the scientific training of PhD and graduate students.
Significance for the country
The proposed project will, in the long run, contribute to the progress of oncology as it introduces completely new concept to treatment and diagnostics of colorectal cancer. The suggested probiotic theranostic bacteria (ProbioTheranostics) will be safe and presumably with little side effects; they could therefore be used as an alternative or adjuvant drug in cancer medicine. The proposed concept of ProbioTheranostics could trigger similar line of research in other fields of medicine in which microbiota plays an important role. We believe the project will lay the foundation for further research work in the field of targeted microbiota manipulation that is beginning to rapidly attract attention of pharmaceutical industry. The establishment of a new approach to bacterial engineering and functionalization will be important in the field of applied microbiology. The approach can be transferred to other microbial species or can be used for non-medicinal applications of lactic acid bacteria, e.g. biocatalysis. The project will contribute to the development of biotechnology, particularly to the biotechnology of lactic acid bacteria, as it will introduce new genetic engineering techniques, such as CRISPR-Cas mediated genome engineering and inducible double-protein expression system. The proposed project will contribute to the scientific development at the Department of Biotechnology at Jozef Stefan Institute. The project will upgrade the existing research and will create a starting point for further research, focusing on combinatorial treatment and clinical studies. The project will also contribute to the scientific training of PhD and graduate students.
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