Targeting p38-dependent macrophage functions for lung cancer treatment

• Applicant: Anna Brichkina, Ph.D.
• Subject Area: Hematology, Oncology ; Pneumology, Thoracic Surgery ; Cell Biology
• Term: from 2018 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 391332315

Recent scientific efforts demonstrated that an effective approach to treating cancer will require therapies that target both tumor cells and tumor microenvironment. The current project is dedicated to identify new targets within the macrophage component of the tumor microenvironment which could be used as clinical biomarkers and help to design new approaches for lung cancer treatment. Our preliminary data show that constitutive downregulation of p38MAPK signaling in a knock-in mouse model or conditional ablation of p38 in macrophages significantly suppresses KrasG12D driven lung tumorigenesis, indicating that p38 kinase is crucial for macrophage-dependent lung cancer progression. It is the goal of this project to dissect the mechanism for p38-dependent reprogramming of macrophages in lung cancer. We will carry out experiments to identify p38-dependent targets in the activation of tumor-associated macrophages, validate their clinical relevance for lung cancer patients, propose potential approaches in targeting tumor-related functions of macrophages and test any discovered drugs in the KrasG12D driven model of murine lung cancer and human lung cancer xenografts. The project has strong clinical relevance as previous genome-wide bioinformatics analyses of lung cancer specimen have identified p38MAPK signaling as a central hub in lung cancer pathogenesis (Brichkina et al., 2016a). Furthermore, identified targets within the macrophage component and ways of complementary lung cancer treatment based on blocking macrophage activation could be similarly translated to other types of cancers.

• DFG Programme: Research Grants