Introduction: PIK3CB is an isoform of phosphoinositide3-kinase (PI3K) shown to be a biomarker for glioblastoma recurrence. We sought to assess the relationship between PIK3CB expression and recurrence and whether it could provide a novel therapeutic target in the treatment of glioblastoma.
Methods: We assessed for trends in PI3K expression in glioblastoma patients from the TCGA database. We cultured glioblastoma cell lines and analyzed the expression of PIK3CB/p110ß and its role in AKT activation. Genetic knockdown was utilized to silence PIK3CB/p110ß to evaluate the effect on AKT activation. We inoculated tumor cells into immune deficient mice to form subcutaneous xenograft tumors and then treated mice with TGX-221 which is a p110ß inhibitor.
Results: Expression of high levels of PIK3CB showed a statistically significant increase in the incidence of glioblastoma recurrence (P = 0.01), shorted time to tumor recurrence (P = 0.03), and shorter survival after recurrence (P < 0.05). The p110ß isoform of PIK3CB was consistently expressed at high levels which coincided with robust activation of pAKT which is involved in cell survival. We silenced was with shRNA-mediated knockdown and found a 70-80% reduction in p110ß. Silencing PIK3CB/p110ß induced an 80% decrease in pAKT levels and lead to apoptosis. In inoculated mouse studies, TGX-221 significantly decreased the tumor volumes compared to the control (P = 0.029). Tumor growth inhibition (TGI) of TGX-221 was approximately 57.
Conclusions: Higher levels of PIK3CB in glioblastoma are correlated with higher incidence of recurrence, shorter time to recurrence, and worse prognosis of tumor recurrence. Higher levels of PIK3CB/p110ß correlate with phosphorylated AKT levels which is associated with cell survival. TGX-221, a selective inhibitor of PIK3CB/p110ß, suppresses AKT activation and inhibits cell survival and glioblastoma growth. Our results demonstrate that PIK3CB/p110ß is an essential survival factor for glioblastoma, and inhibitors like TGX-221 may serve as adjuncts to treatment.
Patient Care: We are looking for methods to battle glioblastoma cell survival and glioblastoma recurrence. Better understanding of tumor survival mechanisms may lead to more effective chemotherapeutic interventions.
Learning Objectives: TO better understand facts involved in glioblastoma recurrence and survival.