Description du projet
Un modèle préclinique innovant de cancer en 3D pour les métastases cérébrales
Le projet 3DBrainStrom, financé par l’UE, vise à établir des modèles de métastases cérébrales imprimés en 3D qui comprennent la matrice extracellulaire du cerveau, le stroma et le sérum contenant des cellules immunitaires circulant dans des vaisseaux fonctionnels. Ces modèles permettront de mieux saisir les propriétés des tissus cliniques, les voies de signalisation, l’hémodynamique et la réactivité aux médicaments. Les chercheurs exploiteront les nouveaux modèles pour concevoir trois approches thérapeutiques visant à cibler les compartiments cellulaires impliqués dans les métastases cérébrales: la prévention de la colonisation métastatique du cerveau à l’aide de nanovaccins ciblés; l’inhibition de l’interaction entre les cellules du stroma cérébral et celles de la tumeur au cours de la progression des micrométastases; et le ciblage sélectif de cellules tumorales. Ces nouveaux modèles précliniques de cancer permettront de combler les lacunes en matière de traduction dans le domaine de la thérapeutique du cancer.
Objectif
Brain metastases represent a major therapeutic challenge. Despite significant breakthroughs in targeted therapies, survival rates of patients with brain metastases remain poor. Nowadays, discovery, development and evaluation of new therapies are performed on human cancer cells grown in 2D on rigid plastic plates followed by in vivo testing in immunodeficient mice. These experimental settings are lacking and constitute a fundamental hurdle for the translation of preclinical discoveries into clinical practice. We propose to establish 3D-printed models of brain metastases (Aim 1), which include brain extracellular matrix, stroma and serum containing immune cells flowing in functional tumor vessels. Our unique models better capture the clinical physio-mechanical tissue properties, signaling pathways, hemodynamics and drug responsiveness. Using our 3D-printed models, we aim to develop two new fronts for identifying novel clinically-relevant molecular drivers (Aim 2) followed by the development of precision nanomedicines (Aim 3). We will exploit our vast experience in anticancer nanomedicines to design three therapeutic approaches that target various cellular compartments involved in brain metastases: 1) Prevention of brain metastatic colonization using targeted nano-vaccines, which elicit antitumor immune response; 2) Intervention of tumor-brain stroma cells crosstalk when brain micrometastases establish; 3) Regression of macrometastatic disease by selectively targeting tumor cells. These approaches will materialize using our libraries of polymeric nanocarriers that selectively accumulate in tumors.
This project will result in a paradigm shift by generating new preclinical cancer models that will bridge the translational gap in cancer therapeutics. The insights and tumor-stroma-targeted nanomedicines developed here will pave the way for prediction of patient outcome, revolutionizing our perception of tumor modelling and consequently the way we prevent and treat cancer.
Champ scientifique
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Régime de financement
ERC-ADG - Advanced GrantInstitution d’accueil
69978 Tel Aviv
Israël