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Sci Transl Med. 2012 Jan 4;4(115):115ra3. doi: 10.1126/scitranslmed.3002977.

Paracrine signaling through MYCN enhances tumor-vascular interactions in neuroblastoma.

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  • 1Biomedical Science Graduate Program, University of California, San Francisco, 1450 Third Street, MC0520, San Francisco, CA 94158-9001, USA.

Abstract

Neuroblastoma, a tumor of peripheral neural crest origin, numbers among the most common childhood cancers. Both amplification of the proto-oncogene MYCN and increased neoangiogenesis mark high-risk disease. Because angiogenesis is regulated by phosphatidylinositol 3-kinase (PI3K), we tested a clinical PI3K inhibitor, NVP-BEZ235, in MYCN-dependent neuroblastoma. NVP-BEZ235 decreased angiogenesis and improved survival in both primary human (highly pretreated recurrent MYCN-amplified orthotopic xenograft) and transgenic mouse models for MYCN-driven neuroblastoma. Using both gain- and loss-of-function approaches, we demonstrated that the antiangiogenic efficacy of NVP-BEZ235 depended critically on MYCN in vitro and in vivo. Thus, clinical PI3K/mammalian target of rapamycin inhibitors drove degradation of MYCN in tumor cells, with secondary paracrine blockade of angiogenesis. Our data demonstrated significantly improved survival in treated animals and suggest that NVP-BEZ235 should be tested in children with high-risk, MYCN-amplified neuroblastoma.

Comment in

PMID:
22218692
[PubMed - indexed for MEDLINE]
PMCID:
PMC3402217
Free PMC Article

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