Activation of PI3K/mTOR pathway occurs in most adult low-grade gliomas and predicts patient survival

Radiation Oncology Program, Harvard Medical School, Boston, MA 02115, USA.
Journal of Neuro-Oncology (Impact Factor: 3.07). 09/2009; 97(1):33-40. DOI: 10.1007/s11060-009-0004-4
Source: PubMed


Recent evidence suggests the Akt-mTOR pathway may play a role in development of low-grade gliomas (LGG). We sought to evaluate whether activation of this pathway correlates with survival in LGG by examining expression patterns of proteins within this pathway. Forty-five LGG tumor specimens from newly diagnosed patients were analyzed for methylation of the putative 5'-promoter region of PTEN using methylation-specific PCR as well as phosphorylation of S6 and PRAS40 and expression of PTEN protein using immunohistochemistry. Relationships between molecular markers and overall survival (OS) were assessed using Kaplan-Meier methods and exact log-rank test. Correlation between molecular markers was determined using the Mann-Whitney U and Spearman Rank Correlation tests. Eight of the 26 patients with methylated PTEN died, as compared to 1 of 19 without methylation. There was a trend towards statistical significance, with PTEN methylated patients having decreased survival (P = 0.128). Eight of 29 patients that expressed phospho-S6 died, whereas all 9 patients lacking p-S6 expression were alive at last follow-up. There was an inverse relationship between expression of phospho-S6 and survival (P = 0.029). There was a trend towards decreased survival in patients expressing phospho-PRAS40 (P = 0.077). Analyses of relationships between molecular markers demonstrated a statistically significant positive correlation between expression of p-S6(235) and p-PRAS40 (P = 0.04); expression of p-S6(240) correlated positively with PTEN methylation (P = 0.04) and negatively with PTEN expression (P = 0.03). Survival of LGG patients correlates with phosphorylation of S6 protein. This relationship supports the use of selective mTOR inhibitors in the treatment of low grade glioma.

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Available from: Michael Prados, Feb 03, 2014
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    • "For example, Cloughesy et al. [13] showed that induction of phospho-PRAS40Thr246 is significantly associated with shorter time to progression in PTEN-deficient glioblastoma patients. McBride et al. [14] identified that there was a trend towards decreased survival in low-grade glioma patients expressing phospho-PRAS40Thr246. These findings were consistent with our results in gastric cancer. "
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    ABSTRACT: Phospho-PRAS40(Thr246) (phosphorylated proline-rich Akt substrate of 40 kilodaltons at Thr246) is a biomarker for phosphatidylinositol 3-kinase (PI3K) pathway activation and AKT inhibitors sensitivity. In this study, we immunohistochemically investigated the expression of phospho-PRAS40(Thr246) in 141 gastric cancer tumors, and evaluated its clinicopathological and prognostic significance. Sixty-four cases (45.4%) were defined as phospho-PRAS40(Thr246) positive. Phospho-PRAS40(Thr246) correlated positively with lymph node metastasis, lymphatic infiltration, vascular infiltration and shorter survival. Furthermore, phospho-PRAS40(Thr246) is an independent prognostic factor for gastric cancer. Our data suggest that phospho-PRAS40(Thr246) was frequently expressed in gastric cancers, and correlated with malignant progression and poor prognosis of patients. PI3K pathway-targeted therapies should be considered in the future treatment of gastric cancers.
    Archives of Medical Science 02/2014; 10(1):149-53. DOI:10.5114/aoms.2013.36927 · 2.03 Impact Factor
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    • "There was also a trend toward decreased survival in patients whose tumors expressed phospho-PRAS40. Phospho-S6 expression correlated with PTEN methylation in these tumors as well (McBride et al., 2010). Also, in a molecular analysis study of 92 pilocytic astrocytomas including 43 conventional pilocytic astrocytomas , 25 clinically aggressive/recurrent pilocytic astrocytomas, and 25 anaplastic pilocytic astrocytomas, an increase in cytoplasmic phosphorylated-Akt (phospho-Akt) and phospho-S6 was associated with anaplastic histology (a more aggressive phenotype ) and poorer outcomes in pilocytic astrocytomas (Rodriguez et al., 2011). "
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    ABSTRACT: Brain tumors are the most common solid pediatric malignancy. For high-grade, recurrent or refractory pediatric brain tumors, radiation therapy (XRT) is an integral treatment modality. In the era of personalized cancer therapy, molecularly targeted agents have been designed to inhibit pathways critical to tumorigenesis. Our evolving knowledge of genetic aberrations in low-grade gliomas is being exploited with targeted inhibitors. These agents are also being combined with XRT to increase their efficacy. In this review, we discuss novel agents targeting three different pathways in low-grade gliomas, and their potential combination with XRT. B-Raf is a kinase in the Ras/Raf/MAPK kinase pathway, which is integral to cellular division, survival and metabolism. In low-grade pediatric gliomas, point mutations in BRAF (BRAF V600E) or a BRAF fusion mutation (KIAA1549:BRAF) causes overactivation of the MEK/MAPK pathway. Pre-clinical data shows cooperation between XRT and tagrgeted inhibitors of BRAF V600E, and MEK and mTOR inhibitors in the gliomas with the BRAF fusion. A second important signaling cascade in pediatric glioma pathogenesis is the PI3 kinase (PI3K)/mTOR pathway. Dual PI3K/mTOR inhibitors are poised to enter studies of pediatric tumors. Finally, many brain tumors express potent stimulators of angiogenesis. Several inhibitors of immunomodulators are currently being evaluated in in clinical trials for the treatment of recurrent or refractory pediatric central nervous system (CNS) tumors. In summary, combinations of these targeted inhibitors with radiation are currently under investigation in both translational bench research and early clinical trials. We summarize the molecular rationale for, and the pre-clinical data supporting the combinations of these targeted agents with other anti-cancer agents and XRT in pediatric gliomas. Parallels are drawn to adult gliomas, and the molecular mechanisms underlying the efficacy of these agents is discussed
    Frontiers in Oncology 05/2013; 3:110. DOI:10.3389/fonc.2013.00110
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    • "Similar finding emerged for p-AKT in the same report and was discussed in Section 2.2. Also, noteworthy is the findings of McBride et al. [35] who used two different antibodies for the activated form of S6 (Table 3). Both antibodies showed the same percentage of immunostaining, and their expressions were strongly correlated, which served as a good internal validation for their IHC (immunohistochemistry) protocol. "
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    ABSTRACT: Astrocytomas, the most common type of gliomas, and especially grade IV glioblastomas are "endowed" with strong proliferation and invasion potentials, high recurrence rate, and poor patients' prognosis. Aberrant signaling of AKT-mTOR (mammalian target of rapamycin) has been implicated in carcinogenesis. This paper is focused on the impact of deregulated AKT-mTOR signaling components in the clinical outcome and prognosis of human astrocytomas. Current therapeutic targeting of astrocytomas with AKT-mTOR inhibitors in preclinical and clinical stage is also discussed, including future perspectives regarding the management of these devastating tumors.
    Neurology Research International 02/2012; 2012:454957. DOI:10.1155/2012/454957
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