Descrizione del progetto
Un innovativo modello preclinico di cancro in 3D per le metastasi cerebrali
Il progetto 3DBrainStrom, finanziato dall’UE, si propone di istituire modelli tridimensionali delle metastasi cerebrali contenenti matrice extracellulare del cervello, stroma e siero al cui interno siano presenti cellule immunitarie che scorrono in vasi funzionali. I modelli consentiranno di acquisire in modo migliore le proprietà cliniche dei tessuti, le vie di segnalazione, l’emodinamica e la reattività dei farmaci. I ricercatori sfrutteranno i nuovi modelli allo scopo di progettare tre approcci terapeutici mirati ai compartimenti cellulari coinvolti nelle metastasi cerebrali: la prevenzione della colonizzazione metastatica del cervello mediante l’impiego di nanovaccini mirati, l’inibizione dell’interazione tra le cellule stromatiche tumorali e cerebrali nel corso del progresso delle micrometastasi e, infine, il targeting selettivo delle cellule cancerose. I nuovi modelli preclinici di cancro colmeranno il divario traslazionale delle terapie antitumorali.
Obiettivo
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.
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Meccanismo di finanziamento
ERC-ADG - Advanced GrantIstituzione ospitante
69978 Tel Aviv
Israele