Targeting PI3K/mTOR signaling exerts potent antitumor activity in pheochromocytoma in vivo

    1. Natalia S Pellegata1
    1. 1Institute for Diabetes and Cancer, Helmholtz Zentrum München, Neuherberg, Germany
    2. 2Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany
    3. 3German Center for Diabetes Research (DZD), Neuherberg, Germany
    4. 4Technische Universität München, Chair of Experimental Genetics, Freising, Germany
    5. 5Department of Pharmaceutical Radiochemistry, Technische Universität München, Garching, Germany
    6. 6Institute for Diagnostic and Interventional Radiology, Klinikum rechts der Isar der Technische Universität München, Munich, Germany
    7. 7Department of Nuclear Medicine, Klinikum rechts der Isar der Technische Universität München, Munich, Germany
    1. Correspondence should be addressed to N S Pellegata; Email: Natalia.pellegata{at}


    Pheochromocytomas (PCCs) are mostly benign tumors, amenable to complete surgical resection. However, 10–17% of cases can become malignant, and once metastasized, there is no curative treatment for this disease. Given the need to identify the effective therapeutic approaches for PCC, we evaluated the antitumor potential of the dual-PI3K/mTOR inhibitor BEZ235 against these tumors. We employed an in vivo model of endogenous PCCs (MENX mutant rats), which closely recapitulate the human tumors. Mutant rats with PCCs were treated with 2 doses of BEZ235 (20 and 30 mg/kg), or with placebo, for 2 weeks. Treatment with BEZ235 induced cytostatic and cytotoxic effects on rat PCCs, which could be appreciated by both staining the tumors ex vivo with appropriate markers and non-invasively by functional imaging (diffusion-weighted magnetic resonance imaging) in vivo. Transcriptomic analyses of tumors from rats treated with BEZ235 or placebo-identified potential mediators of therapy response were performed. Slc6a2, encoding the norepinephrine transporter (NET), was downregulated in a dose-dependent manner by BEZ235 in rat PCCs. Moreover, BEZ235 reduced Slc6a2/NET expression in PCC cell lines (MPC) also. Studies of a BEZ235-resistant derivative of the MPC cell line confirmed that the reduction of NET expression associates with the response to the drug. Reduction of NET expression after BEZ235 treatment in vivo could be monitored by positron emission tomography (PET) using a tracer targeting NET. Altogether, here we demonstrate the efficacy of BEZ235 against PCC in vivo, and show that functional imaging can be employed to monitor the response of PCC to PI3K/mTOR inhibition therapy.

    • Received 19 October 2016
    • Accepted 3 November 2016
    • Made available online as an Accepted Preprint 3 November 2016
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