Development of GPER agonists as a novel therapeutic option for pancreatic cancer

ended

Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, is the fourth-leading cause of cancer related mortality and is predicted to be the second leading cause of cancer death by 2030. Widely regarded as a death sentence, the 5-year survival rate is less than 5% and this figure has not changed over the past four decades due to lack of effective therapies. PDAC develops in a fibrotic setting that hampers drug delivery and modulates immune response & tumour growth/dissemination. Pancreatic stellate cells (PSCs) are the main resident cells in the tumour microenvironment and the drivers of fibrosis. We have recently identified two pathways that mechanically reprogram PSCs and the tumour microenvironment to physiological conditions to inhibit fibrosis, cancer cell invasion, and modulate immune response. One of these mechanisms involves the G protein-coupled estrogen receptor (GPER). Modulating GPER mediated mechanosignalling has emerged as a powerful target in PDAC paving the way to implement new therapeutic approaches, which are so urgently needed. Building on our published data, we plan to demonstrate the efficacy of newly-synthesized compounds to target mechanotransduction of cancer and stromal cells as a therapeutic strategy in PDAC. Within the group of stromal cells, we will focus on: (i) PSCs to target fibrosis, and (ii) tumour associated macrophages, which are known to have tumour-promoting properties. Following this, we want to investigate the efficacy of self-assembling peptide hydrogels to deliver these compounds to pancreatic organoids. The first stage of each work package will be focused on the experimental verification of the efficacy of these compounds to target the different PDAC cell types and how these compounds can be more effectively delivered using hydrogels. Following validation of the proof of concept, we plan to take steps to commercialise these compounds.