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

Project description

A new therapy could change the outcome for millions with pancreatic cancer

The tumour mass comprises a heterogeneous population of cancer cells and their surroundings. A variety of resident and infiltrating host cells, secreted factors and extracellular matrix are collectively known as the tumour microenvironment. In the case of pancreatic ductal adenocarcinoma (PDAC), pancreatic stellate cells (PSCs) are the main resident cells and the drivers of fibrosis. The fibrotic environment has a number of detrimental impacts including decreasing the effectiveness of therapies, impeding the immune response and helping the tumour grow. MechanoGPER has discovered a way to reprogram PSCs and thus the tumour microenvironment to recreate physiological conditions. Now researchers are developing ways to deliver therapies with the ultimate goal of changing the prognosis for PDAC.

Objective

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.

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Coordinator

IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE
Net EU contribution
€ 150 000,00
Address
South kensington campus exhibition road
SW7 2AZ London
United Kingdom

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Region
London Inner London — West Westminster
Activity type
Higher or Secondary Education Establishments
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EU contribution
No data

Beneficiaries (1)