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Targeting IRE1 in disease

Periodic Reporting for period 1 - INSPIRED (Targeting IRE1 in disease)

Período documentado: 2017-01-01 hasta 2018-12-31

As people are living longer diseases such as cancer and neurodegeneration are becoming some of the greatest challenges we face. There is evidence to suggest that IRE1 plays a major role in the development of cancer and neurodegenerative diseases. IRE1’s plays a role at the cusp of cell survival and cell death but despite tremendous progress over recent years in identifying IRE1 as a key driver of pro-survival signalling during conditions of ER stress, these efforts have not yet translated into novel therapeutics. INSPIRED therefore aims to increase understanding of the role the IRE1 plays in cancer and neurodegeneration and apply that knowledge to develop novel therapies and biomarkers and gene signatures.

Cancer and neurodegeneration two of the biggest health challenges facing an aging European population. 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 conditions that are strongly linked with 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. 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 diseases. INSPIRED is important because it aims to better understand the role of IRE1 and the unfolded protein response in cancer and neurodegeneration and develop novel IRE1 based treatments and prognostic/diagnostic markers for these diseases.

INSPIRED 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. This network will identify new IRE1 targets and generate preclinical data to support targeting IRE1 in cancers and neurodegenerative disease. In particular the network aims
1. Develop new small molecule drug compounds that can specifically modulate IRE1’s biological activities
2. Test new and existing IRE1 modulatory drugs using in vitro and in vivo models of cancer and neurodegenerative disease
3. Map out the signalling network controlled by IRE1 to find companion diagnostics for existing and novel drug compounds.
INSPIRED partners have made significant progress in developing new peptideomimmitic and small molecule drug compounds that can specifically modulate IRE1’s biological activities. Using a variety of approaches that include virtual screening, modification of existing compounds to improve efficacy and selectivity, high-throughput screens using natural plant extract libraries and peptidomimetic development a range of novel IRE1 modulators are being identified and characterised by the INSPIRED partners.

New and existing IRE1 modulators have been tested in cancer and neurodegenerative models. The MNKD compound MKC8866 is showing promise in cell and mouse models of triple negative breast cancer (TNBC). Clinically relevant mouse models of Glioblastoma Multiforme (GBM) have been set up and are adding to our knowledge of the role of IRE1 in tumour development and are being used to test IRE1 compounds that cross the blood brain barrier. The 1st generation of IRE1 RNase and Kinase inhibitors are being tested in models of ALS and efforts are ongoing to improve the delivery of IRE1 modulators to the brain. IRE1 modulators are also screened and tested in cellular models of Alzheimer’s disease.

Increasing our knowledge of IRE1 signalling networks is an important aim of the INSPIRED project. Such an understanding can be applied to generate IRE1 activity gene signatures which can be used to stratify patients and identify those who will potentially respond to IRE1 based therapeutics. It will also facilitate the identification of Biomarkers that can be used to follow the activity of IRE1 compounds undergoing clinical development. Work is well underway to achieve this objective and transcriptomic, metabolomic, and lipodomic data has been generated and is currently being integrated. Gene signatures for GBM and TNBC have already been developed and work is underway to identify an IRE1 gene signature that functions in a number of different cancers and also works in neurodegenerative diseases.
Work carried out by the INSPIRED partners has progressed beyond state of the art in a number of areas including:
• Gene signatures have been identified that can potentially stratify cancer patients to identify who would benefit from treatment RE1 modulators
• Biomarkers as a readout of IRE1 activity and IRE1 modulator efficacy are under development
• Novel IRE1 peptideomimetic compounds, IRE1 kinase modulators and IRE1 RNase modulators have been developed and are being tested in animal and cell models of Triple Negative Breast cancer, Glioblastoma Multiforme, Amyotrophic Lateral sclerosis and Alzheimer’s Disease.
This work is supporting the strategy of using IRE1 modulators as a therapeutic strategy for Cancer and Neurodegenerative diseases and providing the preclinical data to bring them closer to clinical development.