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- W4362479063 abstract "<div>Abstract<p>The identification of mammalian target of rapamycin (mTOR) as a major mediator of neurofibromatosis-1 (NF1) tumor growth has led to the initiation of clinical trials using rapamycin analogs. Previous studies from our laboratory have shown that durable responses to rapamycin treatment in a genetically engineered mouse model of <i>Nf1</i> optic glioma require 20 mg/kg/day, whereas only transient tumor growth suppression was observed with 5 mg/kg/day rapamycin despite complete silencing of ribosomal S6 activity. To gain clinically relevant insights into the mechanism underlying this dose-dependent effect, we used <i>Nf1</i>-deficient glial cells <i>in vitro</i> and <i>in vivo</i>. First, there was an exponential relationship between blood and brain rapamycin levels. Second, we show that currently used biomarkers of mTOR pathway inhibition (phospho-S6, phospho-4EBP1, phospho-STAT3, and Jagged-1 levels) and tumor proliferation (Ki67) do not accurately reflect mTOR target inhibition or <i>Nf1</i>-deficient glial growth suppression. Third, the incomplete suppression of <i>Nf1</i>-deficient glial cell proliferation <i>in vivo</i> following 5 mg/kg/day rapamycin treatment reflects mTOR-mediated AKT activation, such that combined 5 mg/kg/day rapamycin and PI3-kinase (PI3K) inhibition or dual PI3K/mTOR inhibition recapitulates the growth suppressive effects of 20 mg/kg/day rapamycin. These new findings argue for the identification of more accurate biomarkers for rapamycin treatment response and provide reference preclinical data for comparing human rapamycin levels with target effects in the brain. <i>Mol Cancer Ther; 10(2); 279–91. ©2011 AACR</i>.</p></div>" @default.
- W4362479063 created "2023-04-05" @default.
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- W4362479063 date "2023-04-03" @default.
- W4362479063 modified "2023-10-18" @default.
- W4362479063 title "Data from Interpreting Mammalian Target of Rapamycin and Cell Growth Inhibition in a Genetically Engineered Mouse Model of <i>Nf1</i>-Deficient Astrocytes" @default.
- W4362479063 doi "https://doi.org/10.1158/1535-7163.c.6535353" @default.
- W4362479063 hasPublicationYear "2023" @default.
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