Abstract 3520: Imaging parameters and molecular correlates as predictive markers of treatment response to mTOR inhibition in adults with recurrent low-grade gliomas.
Authors: Haas-Kogan Daphne , Phillips Joanna J. , Molinaro Annette , Wahl Michael , Mueller Sabine , Weiss William A. , Lupo Janine M. , Berger Mitchel S. , Prados Michael D. , Butowski Nicholas , Clarke Jennifer , Perry Arie , Nelson Sarah J. , Chang Susan 
Published: August 2014

Abstract
Purpose. Activation of the PI3K/mTOR pathway in low-grade gliomas (LGG) provides a rationale for treatment with mTOR inhibitors as in preclinical studies activation of PI3K/AKT/mTOR renders cells more susceptible to mTOR inhibition. In a phase II prospective clinical trial of the mTOR inhibitor everolimus for recurrent LGGs, we performed preliminary analyses to identify early imaging and molecular biomarkers of treatment response.
Methods. Thirty-six patients (of a planned 60 patients) underwent biopsy at the time of recurrence and were then treated with everolimus. Serial multimodal magnetic resonance imagining was done every 2 months; the imaging included anatomic, dynamic contrast enhanced (DCE), perfusion-weighted, diffusion-weighted, and MR spectroscopic imaging. Tumor molecular analyses included IDH1R132H mutations, 1p19q co-deletions, and phosphoprotein analyses of activation of the PI3K/AKT/mTOR and MAPK pathways by immunohistochemistry, including p-S6, p-PRAS40, p-4EBP1, and p-MAPK.
Results. Histologies at original diagnosis were oligodendroglioma (14), astrocyomta (9), oligoastrocytoma (13). At time of recurrence 9/36 patients had transformed to higher-grade disease. Therapy prior to study participation included radiation in 11 and temozolomide in 23. Twelve patients continue on active therapy, 15 have progressed, and the remaining discontinued drug due to toxicity (n=2), poor follow-up (n=1), refusal of further therapy (n=4), or unrelated intercurrent disease (n=2). Fifteen patients had stable disease for over a year, and 4 had stable disease for over 2 years while on treatment, all despite multiple prior recurrences. Six patients have died, 3 of which had high-grade gliomas at recurrence. Analyses of the first 17 accrued patients showed significant changes in parameters estimated from the DCE data in the T2 lesion in subjects who did not progress in the first 6 months; these changes included reductions in the fractional blood volume (median fBV) and vascular permeability (90th percentile Kps) at 4 months (p&lt;0.001 and p=0.04) and 6 months (p=0.001 and p=0.02). Molecular analyses on tissues obtained from the first 23 accrued patients demonstrated that p-PRAS40 staining was associated with improved PFS (log-rank, p=0.03), which is in contradistinction to a cohort of newly diagnosed adult LGGs that was not treated with signaling inhibitors in which p-PRAS40 staining was associated with worse PFS (log-rank, p=0.07).
Conclusions. In patients with recurrent LGGs treated with everolimus, perfusion parameters may represent early markers of treatment response. Apparent “reversal” of association of p-PRAS40 staining with PFS when everolimus is administered suggests that PI3K/AKT/mTOR pathway activation may serve as a predictive marker of response to mTOR inhibition. Accrual continues and overall efficacy results are pending.
Citation Format: Daphne Haas-Kogan, Joanna J. Phillips, Annette Molinaro, Michael Wahl, Sabine Mueller, William A. Weiss, Janine M. Lupo, Mitchel S. Berger, Michael D. Prados, Nicholas Butowski, Jennifer Clarke, Arie Perry, Sarah J. Nelson, Susan Chang. Imaging parameters and molecular correlates as predictive markers of treatment response to mTOR inhibition in adults with recurrent low-grade gliomas. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3520. doi:10.1158/1538-7445.AM2013-3520