Defining the role of GPR34, GPR65 and GPR183 as therapeutic targets in blood cancers

G-protein-coupled receptors (GPCRs) constitute 30% of all drug targets and are often overexpressed and mutated in cancer, including haematological disorders. There is an immediate need for better treatment for patients suffering from peripheral blood cancers. For example, 41% of people diagnosed with Non-Hodgkin Lymphoma are predicted to survive less than 10-years.

In the proposed project, I will focus on the GPCRs GPR34, GPR65 and GPR183.

I have selected these three receptors based on the current literature and my preliminary data which support the hypothesis that they can be potential therapeutic targets.

To test my assumptions, I will develop and employ novel biophysical BRET-based tools to assess ligand-induced conformational changes in GPR34/65/183 together with receptor-mediated G protein activation and recruitment of intracellular transducer proteins. These assays will be used to test the activity of small ligands predicted from large in silico screenings.

Subsequently, I will analyse if up- or down-regulation, and mutations in GPR34/65/183 influence the functions of in vitro cultured cells of haematological origin and healthy B- and T-cells.

My research will provide the first complexed insight into the role of these GPCRs in malignant and normal blood cells, and will aid the discovery of novel compounds with exciting prospects as anti-cancer drugs