Typologie d'actualités: Team Cell Biology, Molecular Targets and Innovative Therapies

La ligue contre le Cancer (The League Against Cancer) supports research carried out at the CBM

Each year, the Grand Ouest Committee of the League Against Cancer actively participates in research by financing a certain number of scientific projects. At the start of 2024, he donated €84,000 to CBM researchers.

3 projects, at the cutting edge of cancer research, have been funded.

"New therapeutic approach in oncology: development of PROTACs targeting LIMK1 and LIMK2 kinases"
Leader: Béatrice Vallée co-leader of the “Cell signaling and neurofibromatosis” team
Partner: Karen Plé, ICOA, UMR7311, CNRS/University of Orléans

The protein kinases, LIMK1 and LIMK2, are involved in cell skeletal remo Their active role in the development of cancers has been shown both in the formation of tumors and in their dissemination and the growth of metastases. Targeting LIMK1 and LIMK2 to develop new anti-cancer therapies is therefore a very relevant strategy.Unfortunately, traditional small chemical molecules inhibiting the activity of LIMK1 and LIMK2 have not passed clinical trials.In our project, we therefore decided to develop a new class of molecules, PROTACs, which allow the destruction of their target directly in the cell. In our case, we target the destruction of LIMK1 and LIMK2 to annihilate their oncological activity. This PROTAC strategy is very innovative and growing. Building on very promising results that have been obtained on other therapeutic targets, we hope to demonstrate the proof of concept of this new approach targeting LIMK1 and LIMK2, and thus open the way to new therapeutic molecules.

This project received the support of the League against Cancer, the Committees of Loiret, Loir-et-Cher and Morbihan, for the sum of €32,000.

“Innovative prostate cancer diagnosis for personalized medicine approaches: intelligent multiplex mapping of SKCa channels using near-infrared emitting lanthanide-based metallacrowns”
Leader: Svetlana ELISEEVA, “Luminescent lanthanide compounds, spectroscopy and optical bioimaging” team

Each patient's tumors are different because each individual is different. It is therefore crucial to take this diversity of tumors into account to develop personalized approaches. Our research work aims to characterize cancerous tumors with the aim of providing more effective treatment to cure cancer.Several specific potassium channels play a major role in the progression of cancerous tumors and are sensitive to therapies. In this project, we are implementing an innovative near-infrared optical imaging approach which will make it possible to establish the precise identity map of these potassium channels for each patient in order to provide personalized treatment.

This project received the support of the League against Cancer of the Committees of Loiret, Loir-et-Cher and Sarthe, for the sum of €30,000.

“Cancer immunotherapy: evaluation of synthetic versus in-cell expressed bispecific di-affibodies”
Leader: Josef Hamacek, head of the “Molecular assemblies and complex systems” team
Partners: Federico Perche, Vincent Aucagne (CBM), Florence Velge-Roussel (NMNS Tours)

Several receptors on the surface of cancer cells may represent potential targets for antibodies with broad neutralization spectrum. The principle of bispecific synergistic antibodies is to bind via a binding site on the surface of the tumor cell and with the other site to a receptor on the surface of the immune effector cell (NK, T lymphocytes).In this context, antibodies can be replaced by affibodies (AfBs) presenting affinities and selectivities for their targets comparable to antibodies, but having smaller size.This project aims to develop bispecific di-AfBs as innovative agents for the diagnosis and immunotherapy of cancer.These complex molecules are made up of two AfBs linked by linkers and can thus target two epitopes. AfBs will bind specifically to the corresponding receptors overexpressed on the surface of cancer cells to block signaling pathways, and to promote the recruitment of effector cells.This concept offers new therapeutic perspectives and makes it possible to optimize interactions with the cell and provoke the immune reaction.

This project received support from the League Against Cancer of the Committees of Loiret, Sarthe and Côtes d’Armor, for the sum of €22,000.

Christophe DELEHEDDE thesis defense

Christophe DELEHEDDE, PhD student in the "Innovative therapies and nanomedicine" team, will defend his thesis on Monday November 6, 2023 at 14:00 p.m. at the Charles Sadron Auditorium, CNRS Campus in Orléans.

Download the thesis defense notice.

Abstract:

Since the release of mRNA vaccines for COVID-19, there has been much interest in mRNA formulations. Even if they have demonstrated their vaccine effectiveness, other issues must be addressed, in particular their selectivity. This concerns the development of specific delivery systems to direct mRNA to organs and cells of interest. An mRNA-complexing polymer/lipid hybrid (LPR, lipopolyplex) was described by our team as being effective for mRNA delivery. The first objective of my thesis was to study the impact of the net charge and the presence of a trimannosylated ligand of an LPR formulation, on the capture and transfection efficiency of dendritic cells. The results show that the quantity of ligand carried by the formulation can have a negative impact on transfection efficiency while increasing internalization. Rapid routing to acidic compartments induces strong activation of PKR and NF -kB molecular sensors. Interestingly, this effect can be counteracted by the use of an mRNA carrying modified nucleosides and presenting a cap 1 type cap inducing increased activation of the mTOR protein. Today, mRNA-based therapies have considerable potential in immunotherapy. The second  objective  of  the  thesis  was  to  develop  different  types  of  lipid  nanoparticles (LNPs  and  lipoplexes)  to  effectively  deliver  mRNA  into  Natural Killer  (NK)  cells  that  are  very  difficult  to  transfect. These formulations allowed high transfection (80%) while preserving cell viability. They allowed efficient delivery of an mRNA encoding the interleukin 2 (IL-2) protein in human NK cell lines (NK-92 and Khyg-1) and human primary cells. An improvement in NK cell proliferation in vitro was measured compared to the use of recombinant IL-2 protein. Furthermore, no negative impact on activation biomarkers and their cytotoxic capacities was observed. These results pave the way for the use of lipid nanoparticles and mRNA for therapeutic strategies using NK cells. Interestingly, these formulations are also very effective in transfecting different types of immune cells (dendritic cells, macrophages, B and T lymphocytes). In addition, they are also effective in mice after being administered by different routes. To conclude, the results obtained highlight the importance of the careful choice of all components of the formulation to obtain good internalization and efficient translation of the mRNA, with a view to its use for different therapies.

Truly life materials?

Physiological characterization of life in Engineered Living Materials by confocal microscopy at single cell resolution.

The CNRS Institute of Chemistry reported this remarkable research on its site. See the article

Engineered Living Materials (ELMs) combine living cells with non-living scaffolds to get life-like characteristics, such as biosensing, growth, and self-repair. Some ELMs are 3D-printed, and called bio-ink. For ELMs to be functional, cells in ELMs has to remain alive and active. However, currently, microorganism physiology in ELMs is still elusive and restrict their use.

Researchers of the team "Cell signalling and neurofibromatosis" reconstituted such bioprinted ELMs by associating the yeast Saccharomyces cerevisiae with the hydrogel Pluronic F-127. Theydeveloped genetically engineered yeast by integrating fluorescent gene whose expression is correlated to a physiological parameter: ATP concentration (metabolism), intracellular pH (growth phase), morphology … These engineered and ratiometric biosensors are effective and allow to assess yeast physiological status in ELM directly in situ by confocal microscopy at single cell scale level. They constitute a valuable tool easy to adapt to any other system by associating them to other materials to evaluate their biocompatibility.

Furthermore, the researchers tested their recently developed copper biosensor embedded into this hydrogel F-127, and showed it is fully functional into this ELM. Yeast biosensor association with hydrogel provides several very interesting advantages such as protecting yeast from contaminations and supplying them with nutrients.

This work allows to establish the proof of concept that F127 associated with engineered yeast S. cerevisiae is a promising ELM in order to develop easy to use whole-cell biosensors able to detect copper directly on samples collected in the environment.

Bojan Žunar B., Ito T., Mosrin C., Sugahara Y., Bénédetti H., Guégan R. and Vallée B.
Confocal imaging of biomarkers at a single-cell resolution: quantifying 'living' in 3D-printable engineered living material based on Pluronic F-127 and yeast Saccharomyces cerevisiae.
Biomater Res 26, 85 (2022). https://doi.org/10.1186/s40824-022-00337-8

The League Against Cancer supports research carried out at the CBM and the INEM

The committees of the Grand Ouest Cancer League bringing together Brittany, Pays de la Loire, Centre-Val de Loire and Poitou-Charentes pool their resources to support cancer researchers.

On Tuesday 7 February at the CBM, La Ligue contre le cancer officially presented a check for €146,000 to support 6 teams of researchers from the CBM and the INEM (Laboratory of Experimental and Molecular Immunology and Neurogenetics). The projects supported aim to quickly achieve concrete results for the benefit of patients.

The committees of Loiret (represented by its volunteer Administrator, Doctor Jean-Louis Vaur) and Eure-et-Loir (represented by its volunteer Vice-President Mr. Jacques Dautreme) were present. The Loir-et-Cher, Cher and Morbihan committees, which are also funders, could not be present but indicated that they were happy to be able to contribute to the financing of regional research.

Mr. Jean-Marc Schneider from La République du Center came to immortalize this moment by going around the table allowing everyone to present their project as well as the benefits and progress to come.