Research ArticleNeuroblastoma

Paracrine Signaling Through MYCN Enhances Tumor-Vascular Interactions in Neuroblastoma

Science Translational Medicine  04 Jan 2012:
Vol. 4, Issue 115, pp. 115ra3
DOI: 10.1126/scitranslmed.3002977

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Childhood Cancers—and MYCN Therapy—Strike a Nerve

It’s easy to become jaded by the current celebrity-advocate overload. But appeals for children suffering from lethal cancers never fail to tug at the heartstrings. Consider the disease neuroblastoma, one of the most common childhood cancers: Nearly half of the cases occur in children under 2 years of age, and treatments for the so-called high-risk version of the disease often fail. But mouse models of neuroblastoma provide a clue: Overexpression of the MYCN proto-oncogene foreshadows treatment failure. Now, Chanthery et al. demonstrate that a drug currently being tested in clinical trials for solid tumors improves survival by targeting the MYCN protein.

This promising drug, NVP-BEZ235, inhibits the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway, which is frequently activated in cancers. NVP-BEZ235 blocked new blood vessel formation (angiogenesis) by tumors and improved survival in two mouse models of neuroblastoma, a xenograft variety developed with primary tumor from patients and a genetic model in which the MYCN gene drives spontaneous tumor formation in mice. The antiangiogenic effect depended in part on function of the MYCN protein, a transcriptional regulator: NVP-BEZ235 therapy spurred degradation of MYCN in tumor cells, which, in turn, produced local (paracrine) effects that inhibited angiogenesis, a process required for tumor growth and metastasis. Future clinical trials will reveal whether NVP-BEZ235 represents a new therapeutic option for MYCN-amplified neuroblastoma—and a chance for sick toddlers to thrive.