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Targeting IRE1 in disease

Periodic Reporting for period 2 - INSPIRED (Targeting IRE1 in disease)

Período documentado: 2019-01-01 hasta 2021-06-30

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.
Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far (For the final period please include an overview of the results and their exploitation and dissemination)

The research goal of the INSPIRED RISE programme was to identify new IRE1 inhibitors and generate preclinical data in in vivo models to support targeting IRE1 in cancer and neurodegenerative disease.

INSPIRED partners have made significant progress in developing new compounds that can specifically modulate IRE1’s biological activities. Using a variety of approaches that include AlphaScreen technology, high throughput 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.

As part of the INSPIRED project, new and existing IRE1 modulators have been tested in cancer and neurodegenerative models. The (now) commercially available inhibitory compound MKC8866 was shown to have a positive impact in cell and mouse models of triple negative breast cancer (TNBC). In addition, its impact in a mouse model of glioblastoma multiforme (GBM) has also been investigated and novel mechanisms of drug delivery into the brain have been explored. The first generation of IRE1 RNase and kinase inhibitors have also been tested in in vivo models of amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease. Issues with drug accessibility to the brain were encountered and second generation drugs were developed to include modifications to optimise blood brain barrier access.

The projects’ endeavours have increased our knowledge of IRE1 signalling networks. To date, activities by project members have revealed that IRE1 regulates metabolic and lipidomic activity in TNBC. In GBM, IRE activity has dual roles with antagonistic outcomes. In addition, the consortium has developed gene signatures for IRE1 in TNBC and GBM which can be used to stratify patients and identify those who will most likely respond to IRE1 based therapeutics. It will also facilitate the identification of biomarkers that can be used to determine the activity of IRE1 compounds undergoing clinical development.

Knowledge dissemination activities within the INSPIRED included in-person network meetings, teleconferences, phone calls and emails between partners. Outreach and dissemination to the public was primarily being achieved through the INSPIRED website ( and twitter account (@InspiredRISE). Two animated educational videos were made that were aimed at the general public and gave an overview of the UPR. These were made with voiceovers in multiple languages, including Greek, German, Portuguese and Italian. Dissemination of research findings to scientific audiences was achieved by 40 high impact publications and several oral and poster presentations by INSPIRED researchers at national and international conferences. INSPIRED partners also organised 4 scientific symposia.
Work carried out by the INSPIRED partners has progressed beyond state of the art in a number of areas including:
• Novel gene signatures have been identified that can stratify cancer patients to identify those who are likely to benefit from treatment with IRE1 modulators
• Biomarkers as a readout of IRE1 activity and IRE1 modulator efficacy have been developed and can be used to determine response to IRE1 modulation
• Novel IRE1 peptidomimetic compounds, IRE1 kinase modulators and IRE1 RNase modulators were tested in animal and cell models of Triple Negative Breast cancer, Glioblastoma Multiforme, Amyotrophic Lateral sclerosis and Alzheimer’s disease. These studies provided pre-clinical evidence that IRE1 modulators could be effective at treating these diseases.

Overall, the progress made by INSPIRED could lead to alterations in treatment strategies for a number of cancers and neurodegenerative diseases. This would have socio-economic impacts by reducing healthcare costs for these diseases and societal impacts by enabling patients to have better health and quality of life for longer.
IRE1 signalling