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Calcium-Sensing Receptor (CaSR): Therapeutics for Non-Communicable Diseases

Periodic Reporting for period 2 - CaSR Biomedicine (Calcium-Sensing Receptor (CaSR): Therapeutics for Non-Communicable Diseases)

Reporting period: 2018-03-01 to 2020-02-29

G-protein coupled receptors (GPCRs) are the largest family of cell-surface proteins in mammals and are crucial for most biological process. The calcium-sensing receptor (CaSR) is a GPCR that plays a key role in regulating serum calcium concentration. The CaSR is present in a range of tissues, where it has several functions e.g. controls hormone release, cell proliferation and differentiation, inflammation. We still don’t know how the CaSR modulates the function of individual cells within these tissues. It is also unclear whether changes in CaSR function contribute to the development and progression of diseases such as asthma, diabetes mellitus, Alzheimer’s disease, and cancer.
Cancers, cardiovascular disease, diabetes, chronic respiratory disorders, and disorders of mental health represent a global health burden. Finding drugs that could treat any of these diseases will have a great societal impact.
The CaSR Biomedicine consortium has brought together 13 academic and industrial groups from 8 EU countries to address the following objectives:
-Scientific obj.: characterise the functions of the CaSR in a range of tissues; investigate how CaSR function is altered in Alzheimer’s disease, inflammatory lung disease, diabetes, cancer; develop and test innovative CaSR-based therapeutic approaches for these major diseases.
-Training obj.: provide high quality state-of-the-art scientific training to 14 early-stage researchers (ESRs).
-European obj.: establish an EU-wide network of researchers working on the CaSR and a worldwide forum for CaSR research, building links to communities studying the role of other GPCRs.
Overview of the results and their exploitation and dissemination:

The CaSR Biomedicine European Training Network, a translational project, examined a single molecule, the CaSR in a range of physiological and pathological processes. The research results have been presented at numerous conferences, in the form of 80 presentations and published in 31 peer-reviewed publications. The quality of the research is mirrored by the 24 awards received by the ESRs. One project led to the filing of a patent.
The project demonstrated that the CaSR is also a phosphate sensor and the scientific results suggest that the repurposing of some of the existing CaSR modulators could improve treatment of major diseases, e.g. inflammatory lung disease, inflammatory bowel disease, or Alzheimer’s disease. Among the exploitable results is the development of several pharmacological active nanobodies targeting the CaSR, identification of modulators of the CaSR that could be used to treat asthma, and of a new compound that could activate the CaSR.

Work Package 1 showed how the CaSR regulates communication processes, known as signalling, within a cell. We focused on developing experimental cell systems for these studies, and established genetically modified cells that have the CaSR present on their surface. The ESRs developed a detailed understanding of how the CaSR interacts with other proteins within normal and cancer cells to influence signalling.
The ESRs have made a substantial breakthrough in demonstrating that the CaSR not only detects calcium, but detects also phosphate, high levels of which cause cardiovascular deaths in patients with chronic kidney disease.
The ESRs developed a three-dimensional model of the CaSR for use in computational drug design to help identification of drugs targeting the CaSR.
We generated nanobodies targeting the CaSR that can be used to correct the activity of the receptor.
We were able also to determine the in vitro pharmacological profile of a loss-of-function CaSR mutation identified in several patients.

Work Package 2 investigated the role of altered CaSR function in major diseases of ageing such as Alzheimer’s disease, inflammatory lung disease, diabetes, and age-related muscle loss. We provided proof-of-concept of efficacy of CaSR-based therapeutics, in some of these diseases. Our studies have demonstrated that the CaSR is present in nerve cells derived from Alzheimer’s disease patients and CaSR inhibitors counteract some characteristics of Alzheimer’s disease in these cells.
We have shown that inhaled CaSR inhibitors were as effective for treating asthma in several mouse models of this disease as inhaled steroids, the current standard-of-care to treat asthma patients.
We have characterised the phenotype of a mouse model of activating CaSR mutations (similar to patients having an inherited disease called Autosomal Dominant Hypocalcaemia type 1) and demonstrated that some of the symptoms, such as impaired glucose tolerance could potentially be corrected by CaSR inhibitors.

Work Package 3 studied whether drugs targeting the CaSR may be used to treat colon and breast cancers and neuroblastoma, a rare childhood cancer of the nervous system. The ESR showed that drugs activating the CaSR reduced the growth of neuroblastoma tumours in mouse models. In another project we showed that drugs inhibiting the CaSR prevented the spread of breast cancer cells to bone. These drugs seem also to be able to reduce the severity of inflammatory bowel disease in preclinical models. One of the ESRs has successfully developed new computer methods involving artificial neural networks to allow the automated detection of cells and tissues by microscopy.
A major goal of CaSR Biomedicine was to establish an overall understanding of the impact of the CaSR in health and disease. We have shown that altered function of the CaSR contributes to diseases of ageing, such as Alzheimer’s disease, asthma and cancer. As a major impact, we were able to demonstrate that drugs targeting the CaSR have the potential to be repurposed for the treatment of these diseases.
-Demonstrating for the first time that the CaSR activity is affected by the phosphate content of the blood, we provided novel treatment avenues for persons with chronic kidney disease.
-We have demonstrated that inhibitors of the CaSR could be used for the treatment of asthma, without the side effects of steroids, drugs currently used for these patients.
-We found that that repurposing CaSR-based drugs may provide new therapeutic avenues also for patients with Alzheimer’s disease, inflammatory bowel disease, neuroblastoma, and breast cancer.
-We have developed new strategies and experimental tools e.g. nanobodies that could trace the CaSR and modify its activity.
-This project also led to the development of new computer methods that allow the automated detection of cells and tissues by microscopy.

This consortium had a strong focus on nurturing emerging talent and allowing early stage scientists to gain transferable skills required for successful careers in academic or industrial biomedical research. To achieve this, all ESRs were exposed to academic, industrial and clinical environments, and were trained in ethics, intellectual property rights, teaching, and entrepreneurship. Thus, CaSR Biomedicine enhanced the professional competencies of young scientists far beyond the standard of conventional PhD programmes.

A further key impact of CaSR Biomedicine was to increase world-wide visibility of the participating researchers thus strengthening the European Research Area in the field of GPCR biology, as well as promoting links between academic research and the industrial biomedical sector.
The ESRs, PIs and Advisory Board of the CasR biomedicine
The ESRs of the CaSR Biomedicine.