Project information


 

Aim

The Interfere to Suppress or Promote IRE1 (INSPIRED) project aims to establish an inter-sectoral, interdisciplinary network of experts in IRE1 biology and drug development, facilitating effective transfer of knowledge and expertise which will drive significant advances in these fields.

 

Background

Cells respond to different types of stress by activating stress response pathways. The cellular response to Endoplasmic Reticulum (ER) stress is an evolutionary conserved process aimed at minimising damage to the cell, but which can ultimately trigger cell death if the damage is too great. ER stress is becoming recognised as a key factor in the development of many cancers and neurodegenerative diseases. Cancer cells often have a dysfunctional stress response that gives them an advantage, allowing them to survive very high levels of stress, while in some cell types a dysfunctional stress response results in excessive cell death e.g. neurodegenerative diseases. IRE1 is a protein that senses stress and activates the ER stress response and is known to control the switch between survival and death. Targeting IRE1 activity with drugs represents a novel way to approach treatment for both of these types of disease.

The INSPIRED project will drive IRE1 focussed research and innovation in cell stress and drug development for cancer and neurodegenerative diseases by forming an interdisciplinary and inter-sectoral network of experts with strong, dynamic and productive interactions. The partners will work together, each bringing their unique expertise, to develop new classes of therapeutics for these common diseases. By fostering a shared culture of research, innovation and collaboration, the participants will accelerate advances in the field of cell stress responses.

The INSPIRED research project will bring together researchers with complementary expertise, skills and ideas in basic biology, medicinal chemistry, animal models of disease, clinical disease, cell biology, bioinformatics and ‘omics’ technologies, all of whom have a strong interest in IRE1 signalling and/or identifying novel ways to approach the treatment of cancer and neurodegenerative disease. Individual participants from the 6 INSPIRED beneficiaries based in 6 countries will be exposed to new and different environments, which will have a positive impact on their careers by broadening their research perspectives and establishing new collaborations and networks.

This network includes a world leader in IRE1 drug development and will build on existing collaborations to create a strong interdisciplinary IRE1 research programme, accelerating advances in the field and leading to a new class of treatments for cancers and neurodegeneration, where there is a clear unmet need. Cancer was the cause of death for 1.281 million persons in the EU-28 in 2011, responsible for more than a quarter of all deaths (26.3%). Neurodegenerative diseases such as Alzheimer’s that cause dementia affect 1.5-2% of the EU population, and this figure is expected to double every 20 years as the population ages, making it one of the leading medical and societal challenges faced by EU society.

Introduction to the research area

ER stress, the Unfolded Protein Response and IRE1

T he endoplasmic reticulum (ER) is the site where most secreted and membrane-bound proteins are synthesised and folded, and an efficient and functional ER is essential for normal cellular function and for survival. Stressful conditions such as hypoxia, starvation or high energy demands (such as in cancer) disturb this protein production factory resulting in the accumulation and aggregation of unfolded proteins (a common feature of neurodegenerative diseases).

There are three major ‘stress sensors’ located in the ER membrane; PERK, ATF6 and IRE1. Under normal conditions, these are maintained in an inactive state, but under stressful conditions, unfolded proteins begin to accumulate, resulting in a domino effect by which each of these stress sensors become activated. A concerted, complex pro-survival response known as the Unfolded Protein Response ensues. The purpose of the unfold protein response is to halt protein production, ramp up the protein folding machinery, remove misfolded proteins and restore normal functioning of the ER. However, if the cell stress persists and cannot be resolved, the cell switches from pro-survival to pro-death signalling.

 

There is strong evidence to suggest that one of the three ER stress sensors, IRE1 (Inositol Requiring Enzyme 1) is a key mediator in the switch from a pro-survival to a pro-death response. As yet, the molecular mechanisms of this are not well understood, but are essential to developing strategies to interfere with the pathological consequences of ER stress associated with disease.

There are clear links between IRE1 and several diseases including a number of cancers and neurodegenerative diseases. IRE1’s role, at the cusp of cell survival and cell death, makes it an attractive target. However, IRE1 is a relatively underexplored therapeutic target in the treatment of these diseases.

Major advances in recent years identifying IRE1 as a key driver of both cancer and neurodegeneration has identified a clinical and market need for effective drugs targeting IRE1. Yet despite the intensification in drug development, preclinical data to support the use of these drugs in the clinic is urgently required. Greater insights into the mechanisms of IRE1 signalling in each disease state is needed, which in turn will identify potential companion biomarkers to monitor the efficacy of these drugs in clinical trials and beyond. Drugs targeting IRE1 fall into two groups – inhibitors and activators

The INSPIRED project will

use omics technologies to address current knowledge gaps and map out the signalling networks controlled by IRE1 in order to find companion diagnostics for existing and novel drug compounds (WP4)

test new and existing IRE1 modulatory drugs in both in vitro and in vivo models of cancer and neurodegenerative diseases (WP3)

establish an inter-sectoral, interdisciplinary network of experts to share knowledge, expertise and unique reagents essential to delineate IRE1 signalling, with the specific aim of developing new small molecule drug compounds that can specifically modulate IRE1’s biological activities (WP2)

Key research outputs of the project will be:

First-generation small molecule IRE1 activators and second-generation IRE1 inhibitors with improved efficacy and tissue specificity that have potential theraputic use in cancers and neurodegenerative disorders respectively (WP2)

Clinically-relevant data on the potential of IRE1 modulators in models of cancer and neurodegenerative disease (WP3).

Comprehensive map of IRE1 signalling pathways which will be used to identify molecular signatures for use as companion diagnostics of IRE1 modulation. (WP4)