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Ref Type Journal Article
PMID (27521448)
Authors Osswald M, Blaes J, Liao Y, Solecki G, Gömmel M, Berghoff AS, Salphati L, Wallin JJ, Phillips HS, Wick W, Winkler F
Title Impact of Blood-Brain Barrier Integrity on Tumor Growth and Therapy Response in Brain Metastases.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 22
Issue 24
Date 2016 Dec 15
URL
Abstract Text The role of blood-brain barrier (BBB) integrity for brain tumor biology and therapy is a matter of debate.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.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.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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown melanoma not applicable GNE-317 Preclinical - Cell line xenograft Actionable In a preclinical study, a melanoma cell line xenograft model demonstrated cell death of metastasized tumor cells within a small region of the brain when treated with GNE-317 (PMID: 27521448). 27521448