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 Nf1
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 Nf1-deficient glial cells in vitro and in vivo. 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 Nf1-deficient glial growth suppression. Third, the incomplete suppression of Nf1-deficient glial cell proliferation in vivo 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.