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

Introduction

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.

Key Protein Interaction

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.

Proposed Therapeutic Approach

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.

Methodology

We developed a thermal shift assay to identify molecules that stabilize the target and inhibit its unfolding. High throughput screening (HTS) of approximately 5,000 molecules resulted in 4 hits with confirmed specific binding by NMR analysis.

Additional Hits

Two additional hits were identified, each through structure-based virtual screening and a peptide-based approach, with confirmed binding through NMR analysis.

Project Aims

In this project, we aim to validate these 6 hits and to provide proof-of-concept evidence of their potential for cancer therapy.

Validation Steps

1. In Vitro Validation: First, we will validate hits in vitro and in cellular assays.
2. Optimization: Second, we will optimize them with medicinal chemists to obtain lead molecules.
3. In Vivo Evaluation: Third, we will evaluate resulting lead molecules in an in vivo mouse breast cancer model.

Expected Outcomes

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-in-class 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.