Targeting PI3K/mTOR signaling exerts potent antitumor activity in pheochromocytoma in vivo.
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.
Institute for Diabetes and CancerHelmholtz Zentrum München, Neuherberg, Germany.
Misu
M
Lee
Institute for Diabetes and CancerHelmholtz Zentrum München, Neuherberg, Germany.
Ninelia
N
Minaskan
Institute for Diabetes and CancerHelmholtz Zentrum München, Neuherberg, Germany.
Tobias
T
Wiedemann
Institute of Experimental GeneticsHelmholtz Zentrum München, Neuherberg, Germany.
Martin
M
Irmler
Institute of Experimental GeneticsHelmholtz Zentrum München, Neuherberg, Germany.|German Center for Diabetes Research (DZD)Neuherberg, Germany.|Technische Universität MünchenChair of Experimental Genetics, Freising, Germany.
Johannes
J
Beckers
Department of Pharmaceutical RadiochemistryTechnische Universität München, Garching, Germany.
Behrooz H
BH
Yousefi
Institute for Diagnostic and Interventional RadiologyKlinikum rechts der Isar der Technische Universität München, Munich, Germany.
Georgios
G
Kaissis
Institute for Diagnostic and Interventional RadiologyKlinikum rechts der Isar der Technische Universität München, Munich, Germany.
Rickmer
R
Braren
Department of Nuclear MedicineKlinikum rechts der Isar der Technische Universität München, Munich, Germany.
Iina
I
Laitinen
Institute for Diabetes and CancerHelmholtz Zentrum München, Neuherberg, Germany Natalia.pellegata@helmholtz-muenchen.de.
Natalia S
NS
Pellegata
D000310:Adrenal Gland Neoplasms / Q000188:drug therapy* / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000235:genetics; D010673:Pheochromocytoma / Q000188:drug therapy* / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use*; D011922:Rats, Mutant Strains; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D007093:Imidazoles; D050484:Norepinephrine Plasma Membrane Transport Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines; C493226:Slc6a2 protein, rat; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; C531198:dactolisib
MENX; NET; PI3K/mTOR inhibition; imaging; pheochromocytoma; predictive biomarker