Treatment with the PI3K inhibitor buparlisib (NVP-BKM120) suppresses the growth of established patient-derived GBM xenografts and prolongs survival in nude rats

Abstract

Glioblastomas (GBMs) are aggressive brain tumours with a dismal prognosis, despite combined surgery, radio- and chemotherapy. Close to 90 % of all GBMs harbour a deregulated PI3K pathway, which is essential in regulating central cellular functions such as proliferation, cell growth, motility and survival. Thus, PI3K represents a potential target for molecular therapy in GBM. We investigated the anti-tumour efficacy of the PI3K inhibitor buparlisib (NVP-BKM120) in GBM cell lines in vitro and in vivo, when treatment was initiated after MRI-confirmed tumour engraftment. We found that buparlisib inhibited glioma cell proliferation in a dose dependent manner, demonstrated by MTS assay, manual cell count and BrdU incorporation. A dose dependent increase in apoptosis was observed through flow cytometric analysis. Furthermore, by immunocytochemistry and western blot, we found a dose dependent inhibition of Akt phosphorylation. Moreover, buparlisib prolonged survival of nude rats harboring human GBM xenografts in three independent studies and reduced the tumours’ volumetric increase, as determined by MRI. In addition, histological analyses of xenograft rat brains showed necrotic areas and change in tumour cell nuclei in buparlisib-treated animals. The rats receiving buparlisib maintained their weight, activity level and food- and water intake. In conclusion, buparlisib effectively inhibits glioma cell proliferation in vitro and growth of human GBM xenografts in nude rats. Moreover, the compound is well tolerated when administered at doses providing anti-tumour efficacy. Thus, buparlisib may have a future role in glioma therapy, and further studies are warranted to validate this compound for human use.Electronic supplementary materialThe online version of this article (doi:10.1007/s11060-016-2158-1) contains supplementary material, which is available to authorized users.

PIK3CA missense mutations promote glioblastoma pathogenesis, but do not enhance targeted PI3K inhibition

“…Buparlisib (BKM120) has been proposed as a potential targeted therapy for GBM [ 30 – 33 ]. It is currently being investigated in a Phase II clinical trial in GBM patients (ClinicalTrials.gov, NCT01339052).…”

BKM120 induces apoptosis and inhibits tumor growth in medulloblastoma

“…Since the blood-brain-barrier limits availability of drugs to the central nervous system (CNS), brain tumors are generally not considered attractive malignancies for initial drug screenings. However, BKM120 penetrates the blood-brain-barrier, and clinical evaluations in glioblastoma are being conducted [ 22 , 23 ]. While a few studies have examined a role of BKM120 in medulloblastoma, [ 24 – 26 ] no clinical studies have been reported.…”

Therapeutic Potential of Autophagy in Glioblastoma Treatment With Phosphoinositide 3-Kinase/Protein Kinase B/Mammalian Target of Rapamycin Signaling Pathway Inhibitors

“…Currently, a new generation of pan-PI3K inhibitors include BKM120 (buparlisib) and PX-866 (sonolisib), which have high stability and low side effects ( 28 , 29 ). Some studies have demonstrated that the treatment with BKM120 also inhibits AKT phosphorylation, leading to the inhibition of glioma cell proliferation ( 30 ). In addition, in vivo studies have shown that BKM120 reduces the volumetric increase of the tumor and prolongs survival of nude rats harboring human GB xenografts ( 30 ).…”

“…Some studies have demonstrated that the treatment with BKM120 also inhibits AKT phosphorylation, leading to the inhibition of glioma cell proliferation ( 30 ). In addition, in vivo studies have shown that BKM120 reduces the volumetric increase of the tumor and prolongs survival of nude rats harboring human GB xenografts ( 30 ).…”