Anti-cancer effect of targeting fibroblast activation protein alpha in glioblastoma through remodeling macrophage phenotype and suppressing tumor progression

Yazhou Miao; Yuxuan Deng; Jinqiu Liu; Jing Wang; Boyi Hu; Shuyu Hao; Herui Wang; Zhe Zhang; Zeping Jin; Yang Zhang; Chunzhao Li; Peng Zhang; Hong Wan; Shaodong Zhang; Jie Feng; Nan Ji

doi:10.1111/cns.14024

Anti-cancer effect of targeting fibroblast activation protein alpha in glioblastoma through remodeling macrophage phenotype and suppressing tumor progression

CNS Neurosci Ther. 2023 Mar;29(3):878-892. doi: 10.1111/cns.14024. Epub 2022 Nov 15.

Authors

Yazhou Miao^{1

2}, Yuxuan Deng^{1

2}, Jinqiu Liu³, Jing Wang³, Boyi Hu³, Shuyu Hao^{1

2}, Herui Wang⁴, Zhe Zhang^{1

2}, Zeping Jin^{1

2}, Yang Zhang^{1

2}, Chunzhao Li^{1

2}, Peng Zhang^{1

2}, Hong Wan³, Shaodong Zhang³, Jie Feng^{3

5}, Nan Ji^{1

2

6}

Affiliations

¹ Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
² National Clinical Research Center for Neurological Diseases (China), Beijing, China.
³ Beijing Neurosurgical Institute, Capital Medical University, Fengtai, Beijing, China.
⁴ Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
⁵ Beijing Cancer Institute, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China.
⁶ Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, School of Engineering Medicine, Beihang University, Beijing, China.

Abstract

Introduction: Glioblastoma (GBM) is the most malignant form of glioma and has a poor median survival time. Fibroblast activation protein alpha (FAP) is a dual-specificity serine protease that is strongly associated with the development and progression of human carcinomas. However, relatively little is known about the function of FAP and its potential as a therapeutic target in GBMs.

Aims: In this study, we aimed to explore the role of FAP in GBM through a series of experiments and to evaluate the therapeutic effect of PT100, a small molecule inhibitor of FAP, on GBM.

Results: Increased FAP expression was associated with poor survival in glioma. In vitro, FAP knockdown inhibited the process of EMT and caused a decrease in the number of M2 macrophages. In vivo, PT100 was confirmed to suppress the progression of GBMs significantly.

Conclusions: FAP could serve as a biomarker and novel therapeutic target for the treatment of GBM and that PT100 is a promising drug for the treatment of GBM.

Keywords: PT100; epithelial-mesenchymal transition; fibroblast activation protein alpha; glioblastoma.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Brain Neoplasms* / metabolism
Cell Line, Tumor
Glioblastoma* / genetics
Glioma*
Humans
Macrophages / pathology
Phenotype
Serine Endopeptidases / genetics

Substances

fibroblast activation protein alpha
Serine Endopeptidases