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Ninelia Minaskan DOI: 10.3252/pso.eu.18ECE.2016 Endocrine tumours and neoplasia A Material and Methods: BEZ235: This compound was kindly supplied by Novartis Pharma and used for in vitro and in vivo studies. Rat PC tissue samples: Sprague-Dawley rats affected by the MENX-syndrome were used for BEZ235 or PEG administration. Rat PCs were used for primary cell culture. Immunostaining: Primary antibodies directed against phospho S6 (S6-S240/244; Cell Signaling Technology), p-AKT (Ser473; Cell Signaling Technology), Ki67 (Dako), activated caspase-3 (Cell Signaling Technology), CD31 (Abcam), NuSAP (Proteintech), VEGFA (Santa Cruz), and NET (MAb Technologies) were used. RT2 profiler PCR array, semiquantitative RT-PCR and quantitative TaqMan RT-PCR: RNA was extracted from the PCs of the BEZ235treated or untreated rats or MPC cells to perform gene expression array analysis or qRT-PCR. Cell proliferation and apoptosis assays: Cell proliferation was measured with WST-1 colorimetric assay (Roche). Apoptosis was measured by assessing the activity of caspase-3/7 using the Caspase-Glo 3/7 Assay Kit (Promega) according to the manufacturer's recommendations. Magnetic resonance imaging: MRI was performed using a 3.0 Tesla clinical MRI system. T2-weighted (T2w) turbo spin echo sequence was performed to assess the tumor volume before and after treatment. Diffusion weighted-MRI (DW-MRI) was performed using a multishot spin echo EPI sequence (with a total of 6 diffusion weightings) to assess the median apparent diffusion coefficient (ADC) value before and after treatment. Abstract: Pheochromocytomas (PCs) are rare highly vascularized neuroendocrine tumors derived from neural crest-derived chromaffin cells located ether in adrenal medulla or sympathetic ganglia (paragangliomas). Although most cases are benign but about 10% of all PCs can become malignant and resistant to conventional chemotherapy or radiotherapy. Therefore, novel therapeutic approaches are required. In this study, we verified the antitumor efficacy of the dual PI3K/mTOR inhibitor BEZ235 in a unique model of bilateral PCs, MENX affected rats (Figure 1) and identified molecular read outs of drug treatment. Genome-wide transcriptome profiling of PCs from drug-treated or placebo-treated rats was conducted, and identified the Slc6a2 gene, encoding the NET protein, as a target of BEZ235, which is inhibited by drug treatment in a dose-dependent manner. Functional analyses confirmed a predictive role for NET expression in the response to PI3K/mTOR inhibition, which can be monitored using NETselective functional positron emission tomography (PET) imaging with 18F-LMI1195. Moreover, BEZ235 reduced Slc6a2/NET expression also in PC cell line, MPC. Norepinephrine transporter (NET) as a predictive marker of response to PI3K/mTOR inhibition in pheochromocytoma