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Team:Montpellier/Description

Team:Montpellier - 2020.igem.org

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Team:Montpellier

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Cancer is a disease that involves an abnormal and uncontrolled cell growth. Cancer is the second mortality cause in the world, responsible for one death out of 6 and 9.6 million casualties in 2018 [1]. The four more common and deadly cancers are prostate cancer, lung cancer, colorectal cancer, and breast cancer [2]. A tumor is a group of abnormal cells that grow uncontrollably and cause cancer.

The goal of our project is to increase cancer treatment efficiency and enhance the survival rate even in the case of late diagnosis.

We were inspired by intriguing projects using engineered bacteria to fight cancer. They rely on bacteria's ability to progress inside tumors with effective targeting and express therapeutic proteins [3,4]. However, bacteria therapy is limited by safety issues such as the quantity you can inject to a patient without triggering a septic shock, the possible toxicity of the bacteria, and its influence on existing microbiomes. We decided to expand our project on bacteria capacity to produce oncolytic proteins without having to inject them.

Our project leverages the recently described tumor-associated microbiome [5]. The bacteria inside it are specific to the tumor’s location and adapted to its environment. We thought that they were perfect for producing therapeutic protein next to cancer cells and so our project emerged:

Using a bacteriophage vector, we want to reprogram intratumoral bacteria and transform them into cancer fighters. This method lowers the number of safety issues - bacteriophages are solely specific of bacteria and therefore have very low inherent toxicity for humans [6,7] - and the microbiome will suffer minimal changes. We also took special care to choose therapeutic proteins (anti-cancerous protein, monoclonal antibodies…) with minimal chance of mistarget.

We chose various therapeutic genes encoding proteins having different mechanisms of action: (i) cyclic di-AMP ( CDA) enzymes that are agonists for the receptors involved in the cGAS-STING pathway and thus produce interferons that will promote apoptosis in the cancer cells and stimulate the immune response. (ii) cytotoxic (oncolytic) peptides like azurin, and (iii) monoclonal antibodies that have a more direct action on the immune system.

By using a combination of specific promoters and kill switch to restrain protein expression to the tumor, and proteins able to kill cancer cells and reactivate the immune system we’ll achieve maximum safety and tumor clearance.

In order to manage this our project is divided in two years:


  1. Year one we’ll focus on obtaining a phage chassis and proof of concept as well as building a model to extrapolate our results.
  2. Year two we’ll implement therapeutic genes and further strengthen our project.



References

[1] World health organisation. Cancer. (consulted 3th October 2020)
[2] Dictionnaire “cancer”. (consulted 17th August)
[3] Forbes NS. Engineering the perfect (bacterial) cancer therapy. Nat Rev Cancer. 2010
[4] Mansour Sedighi et al. Therapeutic bacteria to combat cancer; current advances, challenges, and opportunities. Cancer medicine 2019
[5] D. Nejman et al. The Human tumor microbiome is composed of tumor type-specific intracellular bacteria. Science. (29th May 2020)
[6] Alexander Sulakvelidze et al. bacteriophage therapy. American society for microbiology, 2001
[7] Anna Colavecchio and Lawrence D Goodridge. Phage Therapy Approaches to Reducing Pathogen Persistence and Transmission in Animal Production Environments: Opportunities and Challenges. Microbiol Spectr 2017