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

Descripción del proyecto

Atacar la rigidez tumoral

Los tejidos son rígidos por naturaleza, lo que les permite percibir y responder a fuerzas mecánicas y resistir la deformación. Esta rigidez depende de la composición del tejido y de la matriz extracelular. En muchos tumores sólidos, el aumento de la rigidez impulsa la progresión del cáncer. El equipo del proyecto INTROPY, financiado por el Consejo Europeo de Investigación, se centra en una proteína que se despliega específicamente en tejidos rígidos, lo que representa una nueva diana terapéutica. En el proyecto se pretende inhibir esta proteína para bloquear la progresión del cáncer impulsada por la rigidez. El equipo de investigación pondrá a prueba compuestos prometedores en modelos celulares, optimizará sus propiedades con química médica y aportará pruebas de concepto de su potencial como tratamientos de primera línea.

Objetivo

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.