Descripción del proyecto
Innovador modelo de cáncer preclínico en 3D de la metástasis encefálica
El proyecto 3DBrainStrom, financiado con fondos europeos, pretende establecer modelos impresos en tres dimensiones (3D) de metástasis encefálicas que incluyen la matriz extracelular del encéfalo, el estroma y el suero que contiene células inmunitarias que fluyen en vasos funcionales. Los modelos representarán mejor las propiedades tisulares clínicas, las rutas de señalización, la hemodinámica y la respuesta a los fármacos. Los investigadores aprovecharán los nuevos modelos para diseñar tres enfoques terapéuticos que actúan de forma selectiva en compartimentos celulares implicados en las metástasis encefálicas: la prevención de la colonización metastásica del encéfalo mediante nanovacunas; la inhibición de la interferencia de las células estromales durante la progresión de micrometástasis; y la identificación selectiva de las células tumorales. Los nuevos modelos preclínicos de cáncer acortarán la brecha traslacional en la terapéutica del cáncer.
Objetivo
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.
Ámbito científico
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Programa(s)
Régimen de financiación
ERC-ADG - Advanced GrantInstitución de acogida
69978 Tel Aviv
Israel