INhibiting mechanoTRansduction as a novel approach for Oncology theraPY (INTROPY)

Projektbeschreibung

Die Tumorsteifigkeit im Visier

Gewebe weisen eine natürliche Steifigkeit auf, die es ihnen ermöglicht, mechanische Kräfte zu detektieren, darauf zu reagieren und Verformungen zu widerstehen. Diese Steifigkeit hängt von der Zusammensetzung des Gewebes und seiner extrazellulären Matrix ab. Bei vielen soliden Tumoren fördert eine erhöhte Steifigkeit das Fortschreiten von Krebserkrankungen. Das ERC-finanzierte INTROPY-Projekt konzentriert sich auf ein Protein, das sich spezifisch in steifem Gewebe entfaltet und ein neuartiges Therapieziel darstellt. Das Projekt soll dieses Protein hemmen, um das steifigkeitsbedingte Fortschreiten von Krebserkrankungen zu verhindern. Das Forschungsteam wird vielversprechende Verbindungen in Zellmodellen erproben, ihre Eigenschaften mittels medizinischer Chemie optimieren und einen Wirksamkeitsnachweis für ihr Potenzial als First-in-Class-Therapeutika erbringen.

Ziel

Increased tissue stiffness is a hallmark of many solid tumours, driving tumour progression. This occurs through mechanotransduction, the process by which cells sense and respond to mechanical signals. Our lab has identified a key interaction between two proteins, essential for mechanotransduction. This interaction is triggered by force-induced unfolding of a target protein, which occurs only in stiff tissues. Hence, we propose a novel therapeutic approach that targets mechanotransduction by inhibiting the stiffness-induced unfolding of the target protein. This innovative approach has the potential to transform cancer therapy and provide new insights into the role of mechanical signals in disease progression. We developed a thermal shift assay to identify molecules that stabilize the target and inhibit its unfolding. High throughput Screening (HTS) of ~5,000 molecules resulted in 4 hits with confirmed specific binding by NMR analysis. Two additional hits were identified each through structure-based virtual screening and a peptide-based approach, with confirmed binding through NMR analysis. In this project, we aim to validate these 6 hits, and to provide proof-of-concept evidence of their potential for cancer therapy. First, we will validate hits in vitro and in cellular assays. Second, we will optimize them with medicinal chemists to obtain lead molecules. Third, we will evaluate resulting lead molecules in an in vivo mouse breast cancer model. By the end of the project, we expect our data to be sufficient to attract private investment and establish a spin-off company to pursue drug development into clinical phases. This will lead to a first-inclass mechanoinhibitor drug, with potential applications in cancer (with a focus on breast and pancreatic cancer) and other conditions characterized by mechanical stress, such as fibrosis.