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BACKGROUND: Low-grade gliomas (LGG) are slow growing, primary brain tumors that frequently recur after primary surgical treatment. Recent work has suggested the activation of the PI3K/mTOR pathway in >50% of LGG, raising the possibility that treatment with mTOR inhibitors such as everolimus (RAD001) may benefit patients with LGG. METHODS: We have an ongoing single-institution phase II clinical trial testing everolimus 10 mg daily in patients with recurrent low-grade gliomas. Primary outcome is 6-month progression-free survival (PFS-6). Secondary outcomes include safety, overall survival, overall response rate, and assessment of the correlation between molecular markers and outcome. A molecularly selected phase II clinical trial for newly diagnosed grade II gliomas is now under development; patients' tumors will be evaluated for 1p/19q chromosomal status as well as PRAS-40 and ribosomal S6 activation as markers of mTOR pathway activation. RESULTS: Accrual in the study for recurrent patients is ongoing, with 48 patients enrolled thus far of 60 total planned. Treatment has been well tolerated. Preliminary PFS-6 for those patients accrued thus far is 72%. Preliminary correlation of results with molecular markers raises the possibility that patients treated with everolimus whose tumors have PRAS-40 activation may have improved PFS vs. treated patients with non-activated tumors (p = 0.03). In contrast, patients with PRAS-40 activated tumors in a historical control trended toward worse PFS than patients with non-activated tumors (p = 0.07). Further molecular characterization, including IDH1/IDH2 status and 1p/19q chromosomal status, is also planned. We will provide updated results at the conference, and will also discuss the design of the study under development for newly diagnosed patients. CONCLUSIONS: Inhibition of the PI3K/mTOR pathway by everolimus is a promising avenue of treatment for low-grade gliomas. SECONDARY CATEGORY: Neuropathology & Tumor Biomarkers.

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