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.
