Inhibiting mechanotransduction for the treatment of pancreatic cancer

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.

After identifying peptide-mimetic lead compounds, we carried out initial toxicity, pharmacokinetics, and initial efficacy tests in mice models. The results established the range of tolerated doses that could be employed, and established conditions in which the compound was stable in plasma for almost a day. Initial efficacy tests did not lead to significant effects of the compound in reducing tumour burden. Thereby, the scientific approach had to be reconsidered and we identified a new batch of promising small molecule compounds through computational analyses. We are now designing strategies for experiments at the in vitro and in vivo level to further fund the project. We adjusted the IP strategy during the implementation of the project to achieve the best goal in the valorization and commercialization process.

In terms of exploitation, almost 50 formal presentations of the project were performed to business contacts. All showed high interest upon presentation of proof of concept in vivo efficacy results, and we expect that the new small molecule compounds will have much more chances to be successfully licensed to a pharmaceutical or spin-off company. After this project, we will apply to several other funding sources to fine-tune the development of new drugs targeted to pancreatic cancer and get closer to a new patent application and a successful exploitation of the results through a license agreement.

During the project implementation, several dissemination and communication actions were performed: press release (4), popularised publication (1), training (1), video/film (1), social media (1), website (1), participation in activities organized jointly with other H2020 projects (2), brokerage events (3), pitch event (1), trade fair (1).

As a result of previous knowledge to understand and control mechanical interactions within cells and tissues, and with the aim of bringing it from science to therapy, we have chosen as target a specific highly relevant protein-protein mechanical interaction, and we have developed a compound that we intend to bring to the cancer market. If successful the developed compounds will become a therapy, improving the treatment of pancreatic cancer, and potentially several other types of cancer. Given the dismal survival rates of pancreatic cancer, and the major health problem posed by cancer in general, the potential societal/economic benefit of the project speaks for itself. Once licensed, further development of this project into clinical trials and eventually clinical practice will also include important job opportunities at several levels; inside the in-licensing company, subcontracting companies and even through the creation of a spin-off company if it is required for the project.

A study from the University of Oxford published in the journal Lancet Oncology aimed to estimate the economic burden of cancer in the EU. Cancer cost the EU €126 billion in 2009, with health care accounting for €51·0 billion (40%); and across the EU, the health-care costs of cancer were equivalent to €102 per citizen. While the cost of cardiovascular disease is higher than that for cancer, the higher number of cancer-related deaths in people of working age means the cost of productivity losses due to premature death was nearly twice as high for cancer as that for heart disease. The National Institutes of Health estimated that the overall cost of cancer in 2010 was $263.8 billion, which included $102.8 billion for all healthcare costs; $20.9 billion for indirect morbidity costs (loss of productivity due to illness): and $104.1 billion for indirect mortality costs (loss of productivity due to premature death). The Agency for Healthcare research and Quality (AHRQ) estimates that the direct medical costs (total of all health care costs) for cancer in the US in 2014 were $87.8 billion.

Importantly, such a new small-molecule program developed at this project has much more chances to be successful in terms of licensing and further exploitation. Small-molecule drug development is still the dominant modality, representing 90% of the drugs in the market. Therefore, the economic and societal benefits resulting from this innovation project are enormous. The project will contribute to put Europe in the first positions regarding pancreatic cancer research.

Periodic Reporting for period 1 - TALVIN (Inhibiting mechanotransduction for the treatment of pancreatic cancer)

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