Pancreatic cancer is the fourth cause of cancer-related deaths across the world. Once it is diagnosed, it also has the lowest survival rate of all major cancers, as only 2-10% of diagnosed people survive after five years. Chemotherapy and radiation therapies are well established, but survival rates are still negligible and patients virtually always experience tumour relapse (that is, a return of the tumour after treatment), and resistance to therapies is very frequent. Therefore, a better understanding of the biology of pancreatic cancer is required to identify novel diagnostic and therapeutic opportunities. One such novel opportunity is to target tumour stiffness. Indeed, pancreatic tumours (as most types of solid tumours) are stiffer than normal tissue, and this increased stiffness in fact drives tumour progression.
Mechanical forces transmitted between cells and their microenvironment drive cell function and regulate tumorigenesis (cancer formation). In previous projects, we have recently identified that the interaction between two molecules—the cytoskeletal proteins vinculin and talin—can be inhibited by a peptide (vinculin fragment, VD1) which blocks cell response to mechanical forces, and the activation of a molecule called YAP, which is a transcriptional regulator (that is, it activates specific genes) and is known to play a role both in pancreatic cancer and in cell response to stiffness. Both increased tissue stiffness and YAP activation drive tumor progression in most solid tumors, and thus inhibiting talin/vinculin interactions has a major potential as a therapeutic approach in several solid cancer types.
Taking into account the implications of this protein-protein interaction, we had designed and synthesized novel drugs reproducing the action of the peptide VD1. The experience gained and the lessons learned during the progress of the project has led us to finally propose a higher innovative approach. We have identified a new promising small molecule compound with proven efficacy in the inhibition of the binding between talin and vinculin for the treatment of pancreatic cancer, which have much more chances to be successfully licensed to a pharmaceutical or spin-off company, with the aim of bringing a specific drug to the market. Besides, we have identified a more accurate hot spot prediction of the interaction, and we carried out a very detailed, in depth computational study of novel small molecule compounds.
