Format

Send to

Choose Destination
Clin Cancer Res. 2016 Dec 1;22(23):5818-5828. Epub 2016 Jun 15.

PI3K Pathway Inhibition Achieves Potent Antitumor Activity in Melanoma Brain Metastases In Vitro and In Vivo.

Author information

1
Department of Dermatology, University Hospital Tübingen, Eberhard Karls University, Tübingen, Germany.
2
Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, University Hospital Tübingen, Eberhard Karls University, Tübingen, Germany.
3
Interdisciplinary Division of Neuro-Oncology, Departments of Vascular Neurology & Neurosurgery, Hertie Institute for Clinical Brain Research, University Hospital Tübingen, Eberhard Karls University, Tübingen Germany.
4
Neuro-Oncology Center Tübingen, Comprehensive Cancer Center Tübingen-Stuttgart, Germany.
5
Center for Personalized Medicine, Eberhard Karls University, Tübingen, Germany.
6
German Cancer Consortium (DKTK), DKFZ partner site, Tübingen, Germany.
7
Department of Pathology, University Hospital Tübingen, Eberhard Karls University, Tübingen, Germany.
8
Department of Diagnostic and Interventional Neuroradiology, University Hospital Tübingen, Eberhard Karls University, Tübingen, Germany.
9
Department of Dermatology, Medical Faculty and University Hospital Carl Gustav Carus, TU Dresden, Germany.
10
Center for Regenerative Therapies Dresden, DFG Research Center and Cluster of Excellence, TU Dresden, Germany.
11
National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany.
12
Department of Neurosurgery, Medical Faculty and University Hospital Carl Gustav Carus, TU Dresden, Germany.
13
Department of Pathology, Medical Faculty and University Hospital Carl Gustav Carus, TU Dresden, Germany.
14
Department of Dermatology, University Hospital Zürich, Zürich, Switzerland.
15
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
16
Department of Dermatology, University Hospital Tübingen, Eberhard Karls University, Tübingen, Germany. Friedegund.Meier@uniklinikum-dresden.de.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN AND 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.

PMID:
27307593
DOI:
10.1158/1078-0432.CCR-16-0064
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center