Periodic Reporting for period 1 - CHIRON (The role of the non-canonical death receptor signalling in cancer and immune cells)
Reporting period: 2023-10-01 to 2025-09-30
Although cancer is still a leading cause of death worldwide, major therapeutic advances have been achieved in the last 15 years. These advances were based on a better understanding of the interaction of tumours and immune cells. The immune system is an essential player as it is highly efficient at eliminating abnormal or potentially cancerous cells. When immune cells recognize aberrant cells they ‘tell’ them to commit suicide, which is mediated by death ligands on the surface of immune cells that bind to death receptors (DRs) on the abnormal cells. Consequently, only tumour cells that learned to avoid destruction by immune cells can become clinically relevant. Many tumours not only learned to ignore the suicidal death signal from immune cells but found even ways to use such signals for their own survival. An important example is the interaction of the death ligand TRAIL with its receptors DR4 and DR5. Many tumour cells can alter this death-signal of TRAIL/DR towards a survival signal that even promotes tumour growth and metastases. The CHIRON project aims to better understand how tumour cells divert the TRAIL/DR-death signal towards a survival signal. This knowledge will be used to develop small molecule inhibitors to block this diversion. By blocking the survival pathway, the tumour cells will become sensitive again towards the TRAIL/DR-induced death signal, offering a novel tool to treat cancers.
(1) Death vs. survival signalling downstream of death receptors: CHIRON uses two advanced methods (APEX2- and GCE/optoproteomic-based proximity labelling) to identify the binding partners of the death receptors DR4 and DR5 in tumour and immune cells, which will provide the most comprehensive analysis to date.
(2) Small molecule inhibitors (SMIs): Our newly developed advanced machine learning tools will allow us to greatly speed up the identification of small molecule inhibitors (SMIs) that can inhibit the hard-to-target protein-protein interactions of the TRAL/DR-survival pathway. By combining this with state-of-the-art chemical synthesis, the efficiency and speed of lead development is greatly accelerated. The efficacy of the developed SMIs will be tested in vitro and in vivo (mouse model).
(3) TRAIL/DR-signalling in the tumour microenvironment: Using a wide range of cellular and in silico approaches, we investigate the role of TRAIL/DR-signalling in the tumour microenvironment and its impact on the patient’s prognosis. This knowledge will allow us, for example, to identify tumour types that can be treated with our SMIs.
(2) Small molecule inhibitors (SMIs): Our newly developed advanced machine learning tools will allow us to greatly speed up the identification of small molecule inhibitors (SMIs) that can inhibit the hard-to-target protein-protein interactions of the TRAL/DR-survival pathway. By combining this with state-of-the-art chemical synthesis, the efficiency and speed of lead development is greatly accelerated. The efficacy of the developed SMIs will be tested in vitro and in vivo (mouse model).
(3) TRAIL/DR-signalling in the tumour microenvironment: Using a wide range of cellular and in silico approaches, we investigate the role of TRAIL/DR-signalling in the tumour microenvironment and its impact on the patient’s prognosis. This knowledge will allow us, for example, to identify tumour types that can be treated with our SMIs.
• The full drug discovery cycle is covered in one project; from in silico compound prediction and synthesis, drug screening, to in vitro validation by cellular and molecular biology and computational tools.
• The project is anticipated to (i) demonstrate the mechanisms, impact, and relevance of the non-canonical DR-signalling in unprecedented detail (cellular, molecular, genetic) and scope (tumour vs. immune cells) and (ii) to develop and verify the efficacy of SMIs (small molecule inhibitors) that re-sensitize tumours toward cell death.
• The project is anticipated to (i) demonstrate the mechanisms, impact, and relevance of the non-canonical DR-signalling in unprecedented detail (cellular, molecular, genetic) and scope (tumour vs. immune cells) and (ii) to develop and verify the efficacy of SMIs (small molecule inhibitors) that re-sensitize tumours toward cell death.