PI3K Pathway Inhibition Achieves Potent Antitumor Activity in Melanoma Brain Metastases In Vitro and In Vivo.
OBJECTIVE
Great advances have recently been made in treating patients with metastatic melanoma. However, existing therapies are less effective on cerebral than extracerebral metastases. This highlights the potential role of the brain environment on tumor progression and drug resistance and underlines the need for "brain-specific" therapies. We previously showed that the PI3K-AKT survival pathway is hyperactivated in brain but not extracerebral melanoma metastases and that astrocyte-conditioned medium activates AKT in melanoma cells in vitro We therefore tested the PI3K inhibitor buparlisib as an antitumor agent for melanoma brain metastases.


RESULTS
Buparlisib inhibited AKT activity, decreased proliferation, and induced apoptosis in metastatic melanoma cell lines and short-term brain melanoma cells, irrespective of their BRAF and NRAS mutation status. In addition, buparlisib inhibited hyperactivated AKT and induced apoptosis in melanoma cells that were stimulated with astrocyte-conditioned medium. The growth of tumors induced by injecting human BRAF- and NRAS-mutant metastatic melanoma cells into the brain of mice was significantly inhibited by buparlisib.


CONCLUSIONS
These results emphasize the value of targeting the PI3K pathway as a strategy to develop drugs for melanoma brain metastases. Clin Cancer Res; 22(23); 5818-28. ©2016 AACR.
Department of Dermatology, University Hospital Tübingen, Eberhard Karls University, Tübingen, Germany.
Heike
H
Niessner
Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, University Hospital Tübingen, Eberhard Karls University, Tübingen, Germany.
Jennifer
J
Schmitz
Interdisciplinary Division of Neuro-Oncology, Departments of Vascular Neurology & Neurosurgery, Hertie Institute for Clinical Brain Research, University Hospital Tübingen, Eberhard Karls University, Tübingen Germany.|Neuro-Oncology Center Tübingen, Comprehensive Cancer Center Tübingen-Stuttgart, Germany.|Center for Personalized Medicine, Eberhard Karls University, Tübingen, Germany.|German Cancer Consortium (DKTK), DKFZ partner site, Tübingen, Germany.
Ghazaleh
G
Tabatabai
Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, University Hospital Tübingen, Eberhard Karls University, Tübingen, Germany.
Andreas M
AM
Schmid
Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, University Hospital Tübingen, Eberhard Karls University, Tübingen, Germany.
Carsten
C
Calaminus
Department of Dermatology, University Hospital Tübingen, Eberhard Karls University, Tübingen, Germany.
Tobias
T
Sinnberg
Department of Dermatology, University Hospital Tübingen, Eberhard Karls University, Tübingen, Germany.
Benjamin
B
Weide
Department of Dermatology, University Hospital Tübingen, Eberhard Karls University, Tübingen, Germany.
Thomas K
TK
Eigentler
Department of Dermatology, University Hospital Tübingen, Eberhard Karls University, Tübingen, Germany.
Claus
C
Garbe
Department of Dermatology, University Hospital Tübingen, Eberhard Karls University, Tübingen, Germany.
Birgit
B
Schittek
Department of Pathology, University Hospital Tübingen, Eberhard Karls University, Tübingen, Germany.
Leticia
L
Quintanilla-Fend
Department of Diagnostic and Interventional Neuroradiology, University Hospital Tübingen, Eberhard Karls University, Tübingen, Germany.
Benjamin
B
Bender
Department of Dermatology, Medical Faculty and University Hospital Carl Gustav Carus, TU Dresden, Germany.|Center for Regenerative Therapies Dresden, DFG Research Center and Cluster of Excellence, TU Dresden, Germany.
Marion
M
Mai
Department of Dermatology, Medical Faculty and University Hospital Carl Gustav Carus, TU Dresden, Germany.|Center for Regenerative Therapies Dresden, DFG Research Center and Cluster of Excellence, TU Dresden, Germany.
Christian
C
Praetorius
Department of Dermatology, Medical Faculty and University Hospital Carl Gustav Carus, TU Dresden, Germany.|National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany.
Stefan
S
Beissert
Department of Neurosurgery, Medical Faculty and University Hospital Carl Gustav Carus, TU Dresden, Germany.|National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany.
Gabriele
G
Schackert
Department of Pathology, Medical Faculty and University Hospital Carl Gustav Carus, TU Dresden, Germany.|National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany.
Michael H
MH
Muders
Department of Pathology, Medical Faculty and University Hospital Carl Gustav Carus, TU Dresden, Germany.|National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany.
Matthias
M
Meinhardt
Department of Pathology, Medical Faculty and University Hospital Carl Gustav Carus, TU Dresden, Germany.|National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany.
Gustavo B
GB
Baretton
Department of Dermatology, University Hospital Zürich, Zürich, Switzerland.
Reinhard
R
Dummer
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
Keith
K
Flaherty
Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, University Hospital Tübingen, Eberhard Karls University, Tübingen, Germany.
Bernd J
BJ
Pichler
Department of Dermatology, Medical Faculty and University Hospital Carl Gustav Carus, TU Dresden, Germany.|Center for Regenerative Therapies Dresden, DFG Research Center and Cluster of Excellence, TU Dresden, Germany.
Dagmar
D
Kulms
Department of Dermatology, Medical Faculty and University Hospital Carl Gustav Carus, TU Dresden, Germany.|Center for Regenerative Therapies Dresden, DFG Research Center and Cluster of Excellence, TU Dresden, Germany.|National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany.
Dana
D
Westphal
Department of Dermatology, University Hospital Tübingen, Eberhard Karls University, Tübingen, Germany. Friedegund.Meier@uniklinikum-dresden.de.|Department of Dermatology, Medical Faculty and University Hospital Carl Gustav Carus, TU Dresden, Germany.|National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany.
Friedegund
F
Meier
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009154:Mutation / Q000187:drug effects; D009362:Neoplasm Metastasis / Q000473:pathology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D000970:Antineoplastic Agents; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt