Abstract
BackgroundPlatelet derived growth factor receptor (PDGFR) activity is deregulated in human GBM due to amplification and rearrangement of the PDGFR-alpha gene locus or overexpression of the PDGF ligand, resulting in the activation of downstream kinases such as phosphatidylinositol 3-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR). Aberrant PDGFR signaling is observed in approximately 25-30% of human GBMs, which are frequently molecularly classified as the proneural subclass. It would be valuable to understand how PDGFR driven GBMs respond to Akt and mTOR inhibition.Methodology/Principal FindingsUsing genetically engineered PTEN-intact and PTEN-deficient PDGF-driven mouse models of GBM that closely mimic the histology and genetics of the human PDGF subgroup, we investigated the effect of inhibiting Akt and mTOR alone or in combination in vitro and in vivo. We used perifosine and CCI-779 to inhibit Akt and mTOR, respectively. Here, we show in vitro data demonstrating that the most effective inhibition of Akt and mTOR activity in both PTEN-intact and PTEN-null primary glioma cell cultures is obtained when using both inhibitors in combination. We next investigated if the effects we observed in culture could be duplicated in vivo by treating mice with gliomas for 5 days. The in vivo treatments with the combination of CCI-779 and perifosine resulted in decreased Akt and mTOR signaling, which correlated to decreased proliferation and increased cell death independent of PTEN status, as monitored by immunoblot analysis, histology and MRI.Conclusions/SignificanceThese findings underline the importance of simultaneously targeting Akt and mTOR to achieve significant down-regulation of the PI3K pathway and support the rationale for testing the perifosine and CCI-779 combination in the human PDGF-subgroup of GBM.
Highlights
Glioblastoma multiforme (GBM) is both the most common and the most malignant primary brain tumor in adults
The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway can be upregulated in gliomas through several mechanisms, most commonly through mutation or loss of heterozygosity of phosphatase and tensin homologue gene (PTEN) or through amplification/over-expression of critical growth factor receptors such as EGFR and Platelet derived growth factor receptor (PDGFR)
Mice develop tumors with a 90– 95% incidence, resulting in the formation of high-grade gliomas within 4–6 weeks post-injection. These tumors share high-grade elements such as microvascular proliferation and pseudopalisading necrosis with human GBMs [34,35] (Fig. 1A,B) These tumors closely mimic the proneural subtype of GBM, in which CDKN2A and PTEN deletion are observed in up to 56% and 69% proneural human gliomas, respectively [36]
Summary
Glioblastoma multiforme (GBM) is both the most common and the most malignant primary brain tumor in adults. Activation of the PI3K pathway is significantly associated with increased tumor grade, decreased levels of apoptosis, and adverse clinical outcome in human gliomas [3]. Akt signals to several downstream targets, including the mammalian target of rapamycin (mTOR). This subsequently leads to increased phosphorylation of eIF4E binding protein 1 (4EBP1) and activation of p70 ribosomal S6 protein kinase (p70S6K), which phosphorylates S6 ribosomal protein [5]. Platelet derived growth factor receptor (PDGFR) activity is deregulated in human GBM due to amplification and rearrangement of the PDGFR-alpha gene locus or overexpression of the PDGF ligand, resulting in the activation of downstream kinases such as phosphatidylinositol 3-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR). It would be valuable to understand how PDGFR driven GBMs respond to Akt and mTOR inhibition
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