Associated with people living longer, diseases such as cancer and neurodegeneration are becoming some of the greatest health challenges we face. Currently, 16% of the European population is over 65, and this figure is expected to reach 25% by 2030. Neurodegenerative diseases are debilitating and largely untreatable terminal conditions that are strongly linked with increasing age. Amongst these disorders, the dementias alone affect over 7 million people in Europe, and this figure is expected to double every 20 years as the population ages. Apart from the incalculable human and societal effects, it currently costs approximately €130 billion per annum to care for people with dementia across Europe, highlighting age-related neurodegenerative disease as one of the leading medical and societal challenges faced by EU society. Cancer is the second leading cause of mortality in EU countries accounting for 26% of all deaths in 2013. It is one of the major contributors to premature deaths in the EU and it has an impact not only on individual health, but also on the economy in terms of lower labour market participation and productivity. There is therefore an urgent need for more effective treatments for these disease types in order to improve health and well being and reduce the economic burden.
The goal of the INSPIRED programme was to improve understanding of the role of a cellular stress response, named the unfolded protein response, in cancer and neurodegeneration. Specifically, the INSPIRED programme explored the role of a protein called IRE1 in the development of cancer and neurodegenerative diseases. In any cell, activation of IRE1 can promote either cell survival or cell death. Thus, IRE1 represents an important protein in a cell that can significantly impact cell fate. Despite excellent progress over recent years in exploring IRE1 biology, these efforts have not yet translated into viable therapeutics. INSPIRED therefore aimed to increase understanding of the role IRE1 plays in cancer and neurodegeneration and apply that knowledge to develop novel therapeutics. In addition, INSPIRED aimed to determine biomarkers and gene signatures indicative of IRE1 activity which could be used to stratify patients in respect to their response to IRE1 modifying drugs.
In order to achieve these aims, a consortium was established that was comprised of an inter-sectoral, interdisciplinary and international network of research groups with complementary expertise in IRE1 biology and drug development, facilitating effective transfer of knowledge and expertise.
The key objectives of the INSPIRED network were:
1. Development of new small molecule drug compounds that can specifically modulate IRE1’s biological activities.
2. Testing of IRE1 modulatory drugs in in vitro and in vivo models of cancer and neurodegenerative disease
3. Delineation of the signalling network controlled by IRE1 in order to identify companion diagnostics for existing and novel drug compounds. IRE1 has two main activities; XBP1 splicing and RIDD. Gene signatures for both have been generated and tested in various disease models.
