The MYCN transcription factor and proto-oncogene contributes to a broad range of pediatric tumors including neuroblastoma, the most common extracranial solid tumor of childhood. Amplification of MYCN occurs in ~25% of neuroblastoma and is associated with high-risk disease in which survival is less than 20%. Tumor angiogenesis is prominent in neuroblastoma and contributes to metastasis, with increased microvascular density also associated inversely with survival.
We hypothesize that angiogenesis in neuroblastoma is triggered in-part by MYCN, that stabilization of MYCN is enhances by PI3K/mTOR and miR-17~92 activations, and that destabilization of MYCN contributes to the efficacy of PI3K inhibitors. In the first part, we show that NVP-BEZ235 decreased angiogenesis and tumor progression. Using both gain and loss of function approaches, we validate that the efficacy of NVP-BEZ235 depends greatly on stability of MYCN.
In the second part, we demonstrate that MYCN stability is enhanced through activation of miR-17~92 (a transcriptional target of MYCN); this in-turn induces a feed forward loop, leading to a highly aggressive pathology of MYCN-driven neuroblastoma. Altogether, these observations argue that NVP-BEZ235 should be tested in children with high-risk, MYCN amplified cancers.