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Targeting Fibroblast Discoidin Domain Receptor 2 for Immunotherapy to Pulmonary Fibrosis

靶向成纤维细胞盘状结构域受体 2 用于肺纤维化免疫治疗

基本信息

批准号：
10362183
负责人：
KEVIN KEEWOUN KIM
金额：
$ 61.84万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10362183
关键词：
1-Phosphatidylinositol 3-Kinase Acute Lung Injury Acute Respiratory Distress Syndrome Antibodies Ants Apoptosis Attenuated Automobile Driving Binding CD94 Antigen Cells Cessation of life Clonal Expansion Collagen Collagen Type I DDR1 gene Data Disease Effector Cell Epithelial Cells Family Feedback Fibrillar Collagen Fibroblasts Fibrosis Future Immunotherapy Lead Lung diseases Malignant Neoplasms Malignant neoplasm of lung Mediating Mesenchymal Modeling Mus Natural Killer Cells PDPK1 gene Pathway interactions Peptides Pharmacology Phosphatidylinositide 3-Kinase Inhibitor Phosphorylation Profibrotic signal Protein Tyrosine Kinase Pulmonary Fibrosis Receptor Protein-Tyrosine Kinases Receptor Signaling Regulation Reporting Resistance Safety Signal Pathway Signal Transduction Surface Syndrome System Systemic Scleroderma T-Lymphocyte Technology Testing Therapeutic Toxic effect Transforming Growth Factor beta Tyrosine Kinase Inhibitor antifibrotic treatment cancer cell cell type chimeric antigen receptor chimeric antigen receptor T cells clinical effect coronary fibrosis discoidin domain receptor 2 engineered NK cell fibrotic lung idiopathic pulmonary fibrosis improved outcome inhibitor member nintedanib novel partial response phosphoproteomics receptor internalization selective expression small molecule inhibitor success therapeutic target

项目摘要

Progressive pulmonary fibrosis is a devastating condition that can lead to rapid death and current therapy is only modestly effective. Tyrosine kinase inhibition with Nindedanib has proven to be a successful therapeutic strategy for a number of pulmonary fibrosis disorders. However, due to the nonspecificity of Nintedanib it is unclear which tyrosine kinases are most critical for driving fibrosis. Future mechanistic studies should focus on identifying specific tyrosine kinases and cell types involved in fibrosis which may enable more precise targeting of critical pro-fibrotic pathways. We have identified discoidin domain receptor 2 (DDR2) as an attractive therapeutic target. DDR2 is a tyrosine kinase receptor activated by fibrillar collagens such as type I collagen and we have recently shown that type I collagen signaling promotes further fibroblast activation leading to a feed forward/postive feedback loop culminating in progressive fibrosis. Furthermore, unlike DDR1, which is highly expressed by many cell types, DDR2 expression is heavily skewed with much higher expression on fibroblasts than other cell types. This is critical because we have recently reported that activation of ubiquitous intracellular signaling pathways can have opposing effects on fibrosis depending on the cell type with pro- fibrotic activation within fibroblasts but anti-fibrotic effects within epithelial cells. Thus, DDR2 may enable more specific targeting of fibroblasts which are the primary fibrogenic effector cells. Recently a novel DDR2-specific inhibitor has been shown to improve outcome in a model of lung cancer through inhibition of cancer associated fibroblasts and DDR2-expressing cancer cells which have undergone mesenchymal transition. In preliminary data we find that this inhibitor is also effective at inhibiting fibrosis. Our preliminary data also support a novel mechanism by which DDR2 signaling regulates PIK3C2α, a poorly understood member of the PI3 kinase family which has recently been shown to regulate TGFβ receptor internalization necessary for TGFβ signaling. PIK3Cα has also been shown to regulate PDK1/Akt signaling consistent with our report that DDR2 regulates fibroblast survival through PDK1/Akt. Finally, a recent report found that targeting fibroblast specific markers using a chimeric antigen receptor (CAR)-T cell approach was effective at attenuating cardiac fibrosis. Collectively, this support our central hypothesis that DDR2 promotes fibrosis through fibroblast specific effects on PIK3C2α/TGFβ signaling, resistance to apoptosis via PIK3C2α/PDK/Akt signaling and that DDR2 represents an attractive target for anti-fibrotic therapy. In addition to testing the importance of DDR2 with a small molecule inhibitor, given skewed high fibroblast expression of DDR2, we will develop CAR-NK cells targeting DDR2 for immunotherapy of pulmonary fibrosis. Unlike T cells, NK cells are not MHC restricted, do not undergo clonal expansion and may therefore serve as off-the shelf therapeutic solution with minimum toxicity. These studies will advance our understanding of a critical pro-fibrotic signaling pathway as well as advance and refine the potential for adapting CAR immunotherapy for fibrosis.

进行性肺纤维化是一种毁灭性的疾病，可导致快速死亡，目前的治疗方法是