Targeting Diacylglycerol Kinase Activity in RAS Mutant Lung Adenocarcinoma
Lead Research Organisation:
The Francis Crick Institute
Department Name: Research
Abstract
Immunotherapies, such as anti-PD-(L)1 and anti-CTLA-4 treatment, created a paradigm shift for the treatment lung cancer. However, these therapies have only demonstrated an effective and durable response in a small subset of patients. Currently most of these therapies target the T lymphocytes residing within tumours. Therefore, to improve the effectiveness of these treatments in lung cancer, we need to expand our methods beyond T cells and target other immune populations also residing in the tumour microenvironment (TME) which can aid in tumour cell elimination (e.g B cells). Reinvigorating lymphocytes by targeting common internal signalling pathways, such as the diacylglycerol (DAG) signalling axis, within these cells is one possible approach to consider.
TarDigRAde (Targeting Diacylglycerol kinase activity in RAS mutant lung adenocarcinoma) is a study designed to investigate how the DAG signalling pathways are altered in immune cells that have been exposed to tumours compared with tumour-naïve cells. Furthermore, it will explore how overactivation of this pathway will impact the immune composition of the TME and determine the efficacy of using this as a strategy in combination with current standard-of-care treatments for lung cancer to improve tumour responses and patient outcomes.
To do so, I will utilise novel small molecule inhibitors that block the action of diacylglycerol kinases, which convert DAG to phosphatidic acid thereby reducing the level of DAG within cells. I will explore the impact of inhibiting this pathway in 3 novel murine models that faithfully recapitulate the 3 major TMEs. I will focus on the composition of the immune cells within the TME, and the activation and functional states of the immune cells present by using techniques including flow cytometry, RNA sequencing, and multiplexed immunohistochemistry. Finally, I will explore if these inhibitors can be used in combination with standard treatments in vivo to enhance therapeutic outcomes.
TarDigRAde (Targeting Diacylglycerol kinase activity in RAS mutant lung adenocarcinoma) is a study designed to investigate how the DAG signalling pathways are altered in immune cells that have been exposed to tumours compared with tumour-naïve cells. Furthermore, it will explore how overactivation of this pathway will impact the immune composition of the TME and determine the efficacy of using this as a strategy in combination with current standard-of-care treatments for lung cancer to improve tumour responses and patient outcomes.
To do so, I will utilise novel small molecule inhibitors that block the action of diacylglycerol kinases, which convert DAG to phosphatidic acid thereby reducing the level of DAG within cells. I will explore the impact of inhibiting this pathway in 3 novel murine models that faithfully recapitulate the 3 major TMEs. I will focus on the composition of the immune cells within the TME, and the activation and functional states of the immune cells present by using techniques including flow cytometry, RNA sequencing, and multiplexed immunohistochemistry. Finally, I will explore if these inhibitors can be used in combination with standard treatments in vivo to enhance therapeutic outcomes.
