Treatment with the PI3K inhibitor buparlisib (NVP-BKM120) suppresses the growth of established patient-derived GBM xenografts and prolongs survival in nude rats.
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.
Oncomatrix Research Lab, Department of Biomedicine, University of Bergen, Bergen, Norway.
I A
IA
Netland
Oncomatrix Research Lab, Department of Biomedicine, University of Bergen, Bergen, Norway.
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HE
Førde
Oncomatrix Research Lab, Department of Biomedicine, University of Bergen, Bergen, Norway.
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Sleire
Oncomatrix Research Lab, Department of Biomedicine, University of Bergen, Bergen, Norway.|Neuro Clinic, Haukeland University Hospital, Bergen, Norway.
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Leiss
Oncomatrix Research Lab, Department of Biomedicine, University of Bergen, Bergen, Norway.
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MA
Rahman
Department of Clinical Medicine, K1, University of Bergen, Bergen, Norway.
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BS
Skeie
Department of Biomedicine, Kristian Gerhard Jebsen Brain Tumour Research Center, University of Bergen, Bergen, Norway.|Department of Pathology, Haukeland University Hospital, Bergen, Norway.
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Miletic
Oncomatrix Research Lab, Department of Biomedicine, University of Bergen, Bergen, Norway.|Department of Biomedicine, Kristian Gerhard Jebsen Brain Tumour Research Center, University of Bergen, Bergen, Norway.|Department of Neurosurgery, Haukeland University Hospital, Bergen, Norway.
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Enger
Department of Biomedicine, Kristian Gerhard Jebsen Brain Tumour Research Center, University of Bergen, Bergen, Norway. dorota@goplen.net.|Department of Oncology, Haukeland University Hospital, Bergen, Norway. dorota@goplen.net.
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Goplen
D000631:Aminopyridines / Q000008:administration & dosage* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D009025:Morpholines / Q000008:administration & dosage* / Q000627:therapeutic use; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011923:Rats, Nude; D016019:Survival Analysis; D023041:Xenograft Model Antitumor Assays
D000631:Aminopyridines; D000970:Antineoplastic Agents; D009025:Morpholines; C571178:NVP-BKM120; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt
Brain tumours; Glioblastoma; PI3K; Patient-derived xenograft; Proliferation; Targeted therapy