title: Preclinical investigation of ibrutinib, a Bruton's kinase tyrosine (Btk) inhibitor, in suppressing glioma tumorigenesis and stem cell phenotypes.
abstract: Standard interventions for glioma include surgery, radiation and chemotherapies but the prognosis for malignant cases such as glioblastoma multiforme remain grim. Even with targeted therapeutic agent, bevacitumab, malignant glioma often develops resistance and recurrence. Thus, developing alternative interventions (therapeutic targets, biomarkers) is urgently required. Bruton's tyrosine kinase (Btk) has been long implicated in B cell malignancies but surprisingly it has recently been shown to also play a tumorigenic role in solid tumors such as ovarian and prostate cancer. Bioinformatics data indicates that Btk is significantly higher in clinical glioma samples as compared to normal brain cells and Btk expression level is associated with stage progression. This prompts us to investigate the potential role of Btk as a therapeutic target for glioma. Here, we demonstrate Btk expression is associated with GBM tumorigenesis. Down-regulation of Btk in GBM cell lines showed a significantly reduced abilities in colony formation, migration and GBM sphere-forming potential. Mechanistically, Btk-silenced cells showed a concomitant reduction in the expression of CD133 and Akt/mTOR signaling. In parallel, Ibrutinib (a Btk inhibitor) treatment led to a similar anti-tumorigenic response. Using xenograft mouse model, tumorigenesis was significantly reduced in Btk-silenced or ibrutinib-treated mice as compared to control counterparts. Finally, our glioma tissue microarray analysis indicated a higher Btk staining in the malignant tumors than less malignant and normal brain tissues. Collectively, Btk may represent a novel therapeutic target for glioma and ibrunitib may be used as an adjuvant treatment for malignant GBM.
authors: The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan.|Division of Neurosurgery, Department of Surgery, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.|Department of Neurology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors: Li
authors: L
authors: Wei
authors: Department of Neurology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors: Yu-Kai
authors: YK
authors: Su
authors: Department of Neurology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Division of Neurosurgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan.
authors: Chien-Min
authors: CM
authors: Lin
authors: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors: Tsu-Yi
authors: TY
authors: Chao
authors: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Department of Neurology, Taiwan Adventist Hospital, Taipei, Taiwan.
authors: Shang-Pen
authors: SP
authors: Huang
authors: Center for Molecular Biomedicine, University of Medicine and Pharmacy, HoChiMinh City, Vietnam.
authors: Thanh-Tuan
authors: TT
authors: Huynh
authors: The Department of Medical Laboratory and Biotechnology, Central Taiwan University of Science and Technology, Taichung, Taiwan.
authors: Hsun-Jin
authors: HJ
authors: Jan
authors: Division of Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Center of Excellence for Cancer Research, Taipei Medical University, Taipei, Taiwan.
authors: Jacqueline
authors: J
authors: Whang-Peng
authors: Department of Radiation Oncology, Taipei Medical University Hospital, Taipei, Taiwan.|Department of Radiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors: Jeng-Fong
authors: JF
authors: Chiou
authors: The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan.
authors: Alexander T H
authors: AT
authors: Wu
authors: Genomics Research Center, Academia Sinica, Taipei, Taiwan.|Department of Biochemistry, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors: Michael
authors: M
authors: Hsiao
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000328:Adult; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000368:Aged; D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D010641:Phenotype; D010880:Piperidines; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse; D000225:Adenine
keywords: Bruton’s tyrosine kinase; cancer stem cells; glioma; ibrutinib