Typologie d'actualités: Team Chemistry, Imaging and Exobiology

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.

The study of terrestrial fossils in ancient rocks: a crucial approach to identify potential signs of life on Mars

The NASA Perseverance rover is actively exploring Jezero Crater, analyzing igneous and sedimentary rocks from the crater floor and delta deposits. The rock samples that will be returned by the Mars Sample Return (MSR) mission in the 2030s will be subjected to detailed laboratory studies.

Some samples may contain traces of ancient Martian life, which are challenging to detect due to their morphological simplicity and subtle geochemical expressions. Using volcanic sediments from Kitty’s Gap Chert (Pilbara, Australia) of 3.45 billion years as analogues, researchers detail the steps needed to demonstrate their syngenicity and biogenicity. Various analytical methods, including optical and electron microscopy, Raman spectroscopy, X-ray fluorescence spectroscopy, and mass spectrometry, have been employed at different scales. Sedimentological, petrological, mineralogical, and geochemical analyses document a coastal environment of deposition, consistent with the development of microbial life. Morphological, elemental, and molecular analyses of carbonaceous matter associated with potential fossil remnants reveal enrichment in bioessential trace metals (V, Cr, Fe, Co, etc.) and colocalized aromatic and aliphatic molecules of biological origin. This study illustrates the analytical protocol necessary to optimize the detection of fossil traces of life in Martian rocks.

This work is reported on the CNRS Chimie website

Reference
Multi-Technique Characterization of 3.45 Ga Microfossils on Earth: A Key Approach to Detect Possible Traces of Life in Returned Samples from Mars
Laura Clodoré, Frédéric Foucher, Keyron Hickman-Lewis, Stéphanie Sorieul, Jean Jouve, Matthieu Réfrégiers, Guillaume Collet, Stéphane Petoud, Bernard Gratuze, Frances Westall
Astrobiology 2024
http://doi.org/10.1089/ast.2023.0089

Enzymatic detection in near infrared optical imaging and MRI with a single ligand complexed to different lanthanide ions

The imaging visualization of active enzymes is of primary importance in biology.

In a collaborative effort between the Centre of Molecular Biophysics (CBM) and the Institute of Chemistry of Natural Substances (ICSN) in Gif sur Yvette, CBM researchers have designed Ln3+ complexes that provide enzyme-mediated changes in NIR luminescence, as well as in Chemical Exchange Saturation Transfer (CEST) and classical T1-weighted MRI, depending on the Ln3+ used. They have demonstrated the successful monitoring of b-galactosidase activity over time in NIR luminescence and CEST MR imaging in phantoms containing the Yb-complex, and in T1 MRI when using the Gd-analogue. A further great advantage of their probe design is its high versatility, as there are a large number of enzymatically cleavable groups that could be attached to the same core, thus creating probes for other important enzyme targets.

Reference : Rémy Jouclas, Sophie Laine, Svetlana V. Eliseeva, Jérémie Mandel, Frédéric Szeremeta, Pascal Retailleau, Jiefang He, Jean-Francois Gallard, Agnès Pallier, Célia S. Bonnet, Stéphane Petoud, Philippe Durand, Éva Tóth
Lanthanide-Based Probes for Imaging Detection of Enzyme Activities by NIR Luminescence, T1- and ParaCEST MRI
Angew. Chem. Int. Ed. 2024, https://onlinelibrary.wiley.com/doi/10.1002/anie.202317728

Marie Curie Postdoctoral Fellowships

Rafael Aroso, from the University of Coimbra, Portugal, will join the “Metal Complexes and MRI” team. Its “PorphIRON” project aims to develop paramagnetic complexes based on transition metals, such as iron, for MRI applications. This work is part of the team's efforts to replace gadolinium, currently used in MRI, with more biocompatible and ecologically more sustainable metals.

Ross Ballantine, from Queen's University Belfast in Northern Ireland, will join the "Synthetic Proteins and Bioorthogonal Chemistry" team to work on the « ThioSHowcase » project. This project aims to explore arylthiol-based amino acids for the chemoselective functionalisation of peptides and of proteins,  with applications in protein labeling and selective peptide cross-linking.

New imaging probe enables MRI detection of early-stage breast cancer tumors

Despite significant progress in cancer imaging and treatment over the years; early diagnosis, metastasis detection, and a better understanding of cancer progression remain an unmet clinical need. Molecular imaging can fulfil this need, but requires the design of contrast agents which target specific tumor biomarkers. Netrin-1 is an extracellular protein overexpressed in metastatic breast, and it is implicated in tumor progression, angiogenesis and appearance of metastasis and tumor aggressivity.

Reserachers of the team "Metal complexes and MRI", develop and validated in vivo the first Netrin-1 specific peptide-based multimodal probe.  A structural validation was performed by molecular docking, thanks to a collaboration CBM and Institute of Organic and Analytical Chemistry.

This probe enabled successful triple-negative metastatic breast tumor visualization namely at early development stage (tumor volume 0-50 mm3), by magnetic resonance imaging (MRI). Such peptide-based probes are molecular platforms allowing imaging by MRI or single photon emission tomography. This bimodal approach makes it possible to scan a wide range of target concentrations (nM to μM), enabling in vivo mapping of Netrin-1 in cancer murine models, at different tumor evolution stages.

References:
Clémentine Moreau, Tea Lukačević, Agnès Pallier, Julien Sobilo, Samia Aci-Sèche, Norbert Garnier, Sandra Même, Éva Tóth and Sara LacerdaPeptide-Conjugated MRI Probe Targeted to Netrin-1, a Novel Metastatic Breast Cancer Biomarker
Bioconjugate Chem. https://doi.org/10.1021/acs.bioconjchem.3c00558