In neuroblastoma (NB), an embryonic tumor of the sympathetic nervous system, amplification of the NMYC oncogene is associated with advanced-stage disease, rapid tumor progression, and poor survival. Here we show that rapamycin and the prodrug CCI-779, both which inhibits mammalian target of rapamycin (mTOR) signalling, effectively reduce the levels of NMYC expression in NB. Expression of pAKT(Ser 473) and pmTOR(Ser2448), suggesting a constitutive activation of the phosphatidylinositol-3 kinase (PI3K)/Akt/mTOR signalling pathway, was detected in all primary NB tumors (28/28) and ganglioneuromas (3/3) investigated but not in non-malignant adrenal medullas. Inhibition of mTOR with rapamycin or CCI-779 inhibited the activation of the downstream mTOR substrates, ribosomal protein S6 kinase 1 (S6K1), 4E-binding protein 1 (4E-BP1) and glycogen synthetase kinase 3 beta (GSK-3β) as well as reduced cyclin D1 and MYCN expression in vitro and in xenografts isolated from nude mice treated with rapamycin or CCI-779. Treatment with rapamycin or CCI-779 reduced proliferation, induced apoptosis and inhibited angiogenesis of NB in vivo, suggesting that both these agents have therapeutic efficacy on NB.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA