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.

Periarteriolar Glioblastoma Stem Cell Niches Express Bone Marrow Hematopoietic Stem Cell Niche Proteins

“…20,99 For example, ibrutinib, a Bruton's tyrosine kinase inhibitor, is promising to target GSCs. 100 Furthermore, proteins involved in invasive behavior and therapy resistance of glioblastoma, such as TROY and SGEF, may well be overexpressed especially in GSCs which warrants further research with respect to specific therapeutic targeting of GSCs. 101,102 Alternatively, interactions between SDF-1α/CXCR4 and OPN/CD44 should be disrupted to enforce GSCs out of their protective niches to sensitize them to chemotherapy and irradiation.…”

High expression of Bruton’s tyrosine kinase (BTK) is required for EGFR-induced NF-κB activation and predicts poor prognosis in human glioma

“…Ibrutinib has recently been shown to have an-tumor activity in some solid cancers [ 23 ]. More recently, BTK has been shown to also play a tumorigenic role in GBM and associate with its sphere-forming potential [ 24 ]. Consistent with the report, we found that ibrutinib can significantly inhibit the proliferation of glioma cells in vitro and in vivo through inducing G1 cell cycle arrest.…”

“…Our results indicate that ibrutinib can be evaluated as novel therapeutic agent for glioma tumor. A recent study demonstrate that the combination of ibrutinib and temozolomide (TMZ) exert more inhibitory effect [ 24 ]. Thus, the combination of TMZ and ibrutinib may be a rational development of therapeutic approaches and clinical trials for glioma treatment.…”

Adenosine-producing regulatory B cells in head and neck cancer

“…The therapeutic potential of ibrutinib in solid tumors is currently being evaluated by a series of research teams including our own group [42][43][44]. However, the prognostic benefit of these molecular changes in patients with solid tumors is still unknown.…”