title: Impact of Blood-Brain Barrier Integrity on Tumor Growth and Therapy Response in Brain Metastases.
abstract: OBJECTIVE
  The role of blood-brain barrier (BBB) integrity for brain tumor biology and therapy is a matter of debate.
  
  
  METHODS
  We developed a new experimental approach using in vivo two-photon imaging of mouse brain metastases originating from a melanoma cell line to investigate the growth kinetics of individual tumor cells in response to systemic delivery of two PI3K/mTOR inhibitors over time, and to study the impact of microregional vascular permeability. The two drugs are closely related but differ regarding a minor chemical modification that greatly increases brain penetration of one drug.
  
  
  RESULTS
  Both inhibitors demonstrated a comparable inhibition of downstream targets and melanoma growth in vitro In vivo, increased BBB permeability to sodium fluorescein was associated with accelerated growth of individual brain metastases. Melanoma metastases with permeable microvessels responded similarly to equivalent doses of both inhibitors. In contrast, metastases with an intact BBB showed an exclusive response to the brain-penetrating inhibitor. The latter was true for macro- and micrometastases, and even single dormant melanoma cells. Nuclear morphology changes and single-cell regression patterns implied that both inhibitors, if extravasated, target not only perivascular melanoma cells but also those distant to blood vessels.
  
  
  CONCLUSIONS
  Our study provides the first direct evidence that nonpermeable brain micro- and macrometastases can effectively be targeted by a drug designed to cross the BBB. Small-molecule inhibitors with these optimized properties are promising agents in preventing or treating brain metastases in patients. Clin Cancer Res; 22(24); 6078-87. ©2016 AACRSee related commentary by Steeg et al., p. 5953.
authors: Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.|Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Matthias
authors: M
authors: Osswald
authors: Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.|Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Jonas
authors: J
authors: Blaes
authors: Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.|Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Yunxiang
authors: Y
authors: Liao
authors: Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.|Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Gergely
authors: G
authors: Solecki
authors: Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.|Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Miriam
authors: M
authors: Gömmel
authors: Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.|Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Anna S
authors: AS
authors: Berghoff
authors: Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California.
authors: Laurent
authors: L
authors: Salphati
authors: Department of Cancer Signaling and Translational Oncology, Genentech, Inc., South San Francisco, California.
authors: Jeffrey J
authors: JJ
authors: Wallin
authors: Department of Cancer Signaling and Translational Oncology, Genentech, Inc., South San Francisco, California.
authors: Heidi S
authors: HS
authors: Phillips
authors: Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.|Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Wolfgang
authors: W
authors: Wick
authors: Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany. frank.winkler@med.uni-heidelberg.de.|Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Frank
authors: F
authors: Winkler
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000502:physiology; D001812:Blood-Brain Barrier / Q000473:pathology*; D001921:Brain / Q000473:pathology*; D001932:Brain Neoplasms / Q000473:pathology*; D002199:Capillary Permeability / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology*; D006801:Humans; D008545:Melanoma / Q000473:pathology; D051379:Mice; D008819:Mice, Nude