Phaeochromocytomas (PCs) are neuroendocrine tumors derived from neural crest-derived chromaffin cells of the adrenal medulla and sympathetic ganglia (the latter referred to as paragangliomas), which produce significant amounts of catecholamines. Although PCs are mostly benign, 10% of all PCs can be malignant evidenced by the presence of metastases, predominantly in bone, lungs, liver and lymph. Currently, there is no effective therapy for malignant PCs.
In many neuroendocrine tumors, including PCs, the PI3K/AKT/mTOR survival pathway is hyperactivated, thereby mediating signals of tumor cell proliferation and survival. Therefore, the inhibition of this signaling cascade may exert an antitumor effect by inhibiting tumor angiogenesis, tumor cell growth and proliferation.
In our study, we evaluated the efficacy of BEZ235, a dual PI3K/mTOR inhibitor, against PC in vivo. We used a dual inhibitor to avoid the re-activation of upstream AKT signaling following mTOR inhibition via a well-documented negative feedback loop. We took advantage of a unique in vivo model of endogenous PCs: MENX-effected rats. We found that BEZ235 exerts antitumor effects on PCs cells. Gene expression analyses of tumors from rats treated with placebo or with BEZ235 identified the Slc6a2 gene as being down-regulated following drug treatment. Slc6a2 encodes the norepinephrine transporter (NET), which is responsible for the intracellular re-uptake of norepinephrine in chromaffin cells. The fact that NET is expressed by PC cells has been extensively exploited for the functional imaging of these tumors using radiolabeled norepinephrine analogues. We observed a dose-dependent reduction of both Slc6a2 (by TaqMan) and NET (by immunohistochemistry) expression in rat PCs following BEZ235 administration, which associated with decreased uptake of the radiolabeled norepinephrine analogue 18F-LMI1195 in vivo.
To assess the relationship between NET levels and response to BEZ235, we generated a drug-resistant derivative of the MPC (mouse PC) cell line. While incubation with BEZ235 reduced NET expression in MPC cells, no reduction was observed in the resistant derivative cells. This suggests that decreased NET expression associates with the ability of PC cells to respond to PI3K/mTOR inhibition.
Altogether, our data demonstrate that targeting PI3K/mTOR signalling is effective against PCs and suggest that NET levels may represent a surrogate marker of therapy response to PI3K/mTOR inhibitors, which can be monitored by functional PET imaging.
17 - 19 Feb 2016
European Society of Endocrinology