Analysis of the role of orphan GPCRs in cancer

GPCRs as drug targets in cancer

"Membranous receptors from the G protein-coupled receptors (GPCRs) family constitute 30-40% of all drug targets” (Hauser, Chavali et al. 2018, Usman, Khawer et al. 2020) is the typical opening sentence of a GPCR-oriented scientific publication. This percentage represents nearly 500 different Food and Drug Administration (FDA)-approved drugs which interact selectively or not selectively with any of 826 human GPCRs. At the same time, there are only seven GPCRs that are targeted by FDA-approved drugs or antibodies against different cancers. This very small group, representing less than 1% of all the GPCRs, consists of dopamine receptor D1 (DRD1), somatostatin receptor (SSTR), Gonadotropin-releasing factor hormone receptor (GnRH), C-X-C chemokine receptor 4 (CXCR4), Estrogen receptor (ER), C-C Chemokine receptor 4 (CCR4) and, most importantly in relation to this grant proposal’s idea, Smoothened (SMO) (Usman, Khawer et al. 2020). This small number feels even more surprising given the extensive research and evidence gathered about the important roles of GPCRs and G proteins in the development and the proliferation of various forms of cancer, with many reports suggesting a role of these proteins as potential prognostic markers (Insel, Sriram et al. 2018, Chaudhary and Kim 2021, Wu, Yung et al. 2023). 

Research questions

Why has the wide knowledge of GPCR expression and signalling paradigms in cancer not been transferred into many therapeutic opportunities?
What is missing to translate this knowledge to effective treatments?

Project includes

  • studying novel protein-protein interactions in cancer cells
  • pharmacological analysis of disease-linked orphan GPCRs mutations
  • development of novel biosensors expressed from endogenous promoters

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