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.
Highlights
Malignant brain tumors are challenging to manage clinically due to the nature of highly resistant to chemotherapy and radiotherapy [1]
Bioinformatics data indicates that Bruton’s tyrosine kinase (Btk) is significantly higher in clinical glioma samples as compared to normal brain cells and Btk expression level is associated with stage progression
Our preliminary search using public databases indicated Btk expression is elevated in advanced GBM clinical samples (Figure 1A)
Summary
Malignant brain tumors are challenging to manage clinically due to the nature of highly resistant to chemotherapy and radiotherapy [1]. Recurrence following standard therapeutic regimens, mainly including surgery, radiation therapy, and adjuvant chemotherapy is virtually inevitable [2]. The standard chemotherapeutic agent such as temozolomide (TMZ) promotes DNA damage and disrupts the brain tumor cell mitotic machinery. It has only limited effect in prolonging patient survival [3]. Accumulating evidence has suggested that malignant glioma stem cells (GSCs), intrinsic and/or therapyinduced, drive tumor formation and treatment resistance [4]. Identifying agents which can target and eliminate GSCs may improve current therapeutic efficacy in GBM patients
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
