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.