Projektbeschreibung
Biomechanische Biomarker zur Vorhersage der Immunantwort auf die Therapie
Da die Krebsimmuntherapie in einigen Fällen schwere Toxizitäten verursacht, sind Biomarker, welche die Non-Responder rechtzeitig vorhersagen können, von großer Bedeutung. Um sich mit diesem Problem auseinanderzusetzen, geht das EU-finanzierte Projekt Immuno-Predictor von der Hypothese aus, dass bestimmte biomechanische Aspekte der Mikroumgebung des Tumors wie Tumorsteifigkeit, Druckstress, Perfusion und Hypoxie für die Resistenz gegen Immuntherapie verantwortlich sind. Die systemische Verabreichung einer Immuntherapie erfordert ein gut durchblutetes Gefäßsystem, das bei Tumorsteifigkeit und sauerstoffarmen Tumoren häufig nicht der Fall ist. Mithilfe klinisch angewandter ultraschallbasierter Methoden und rechnergestützter biomechanischer Modellierung bei tumortragenden Mäusen und Krebspatienten werden Immuno-Predictor-Forschende biomechanische Biomarker bestimmen, um das Ergebnis der Immuntherapie zu prognostizieren.
Ziel
Immunotherapy has revolutionized the treatment of multiple cancers and has already become a standard of care for some tumor types. However, a majority of patients do not benefit from current immunotherapeutics and many develop severe toxicities. Therefore, the identification of biomarkers to classify patients as likely responders or nonresponders to immunotherapy is a timely and of tremendous impact task. My hypothesis is that biomechanical aspects of the tumor microenvironment mediate resistance to immunotherapy. Specifically, many tumors stiffen as they grow and also, tumor growth within the host tissue generates mechanical forces, termed solid stress. Tumor stiffening and solid stress are distinct mechanical abnormalities that compress intratumoral blood vessels, causing hypo-perfusion and hypoxia. Systemic administration of immunotherapeutics requires a well-perfused vasculature, whereas hypo-perfusion and hypoxia promote immunosuppression, helping cancer cells to evade immune responses. The objective of the proposed research is the identification of novel Mechanical Biomarkers related to tumor stiffness, solid stress, perfusion and hypoxia for prediction of immunotherapy. Tumor-bearing mice will be developed and treated with immunotherapeutic drugs and clinically used methods will be combined with computational biomechanical modeling for measuring the Mechanical Biomarkers, making the research transferable to the clinic. The biomarkers will be benchmarked against tumor normalization strategies aiming to restore/normalize mechanical abnormalities and optimize immunotherapy. Finally, the clinical utility of the selected biomarkers will be evaluated in human tumors. Only few tumor-specific biomarkers are used in the clinic - based mainly on genomic analysis. This project is expected to lead to the first biomarkers for immunotherapy prediction exploiting tumor mechanics.
Wissenschaftliches Gebiet
Not validated
Not validated
Programm/Programme
Thema/Themen
Finanzierungsplan
ERC-COG - Consolidator GrantGastgebende Einrichtung
1678 Nicosia
Zypern