Neuroblastoma, a tumor of peripheral neural crest origin, is a common and lethal tumor of childhood. Amplification of the transcription factor MYCN occurs commonly in children with high-risk disease. We generated a model for high-risk, neuroblastoma by directing expression of a MYCN transgene to the peripheral neural crest of genetically engineered mice, under control of the Tyrosine Hydroxylase (TH) promoter. We hypothesize that: 1).Mycn protein plays a central role In high-risk MYCN-ampllfled neuroblastoma. 2). Therapies targeting Mycn will be effective in MYCN-amplified neuroblastoma. 3). Mice transgenic for TH-MYCN and deleted forp53 model high-risk, therapy-resistant neuroblastoma In relapsed patients, and wilt respond to small molecule Inhibitors targeting Mycn. In contrast to applications that propose to screen small molecules to identify one that targets a known molecular lesion, we are starting with two potent and selective phosphatidylinositol-3'kinase (PI3K) inhibitors now in clinical trials that appear ideally suited as therapy against neuroblastoma and Mycn protein. We will characterize the mechanism of action for these agents, analyzing interactions between tumor cells and cells that comprise the microenvironment. We will assess destabilization of Mycn protein, and subsequent impact on tumor burden and survival. We also propose to study and chemically modify a clinical inhibitor of Aurora kinase (AURKA) that already shows promise in neuroblastoma, to build in additional activity against both Mycn protein and drug resistant neuroblastoma.
Our aims are:
Aim 1. To test available clinical PI3K and PI3K/mT0R inhibitors for activity against neuroblastoma and Mycn protein. We hypothesize that these compounds will be effective and safe in patients with MYCN-amplified neuroblastoma.
Aim 2. To clarify additional targets and small molecules that cooperate with inhibitors of PI3K to degrade Mycn. We hypothesize 1). That scaffold-dependent and kinase dependent functions of AurkA contribute independently to the activity of this protein In neuroblastoma. 2). That DFG-out and a-C out inhibitors will disrupt both functions and will show efficacy In neuroblastoma.
Successful completion of this proposal establishes a preclinical rationale for trials in children using clinical PI3K inhibitors, and provides insights into mechanisms of action for inhibitors of PI3K and of AURKA in MYCN-amplified neuroblastoma.
|Johnson, Brett E; Mazor, Tali; Hong, Chibo et al. (2014) Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma. Science 343:189-93|
|Borriello, Lucia; DeClerck, Yves A (2014) [Tumor microenvironment and therapeutic resistance process]. Med Sci (Paris) 30:445-51|
|Gustafson, William Clay; Meyerowitz, Justin Gabriel; Nekritz, Erin A et al. (2014) Drugging MYCN through an allosteric transition in Aurora kinase A. Cancer Cell 26:414-27|
|Kang, Min H; Villablanca, Judith G; Glade Bender, Julia L et al. (2014) Probable fatal drug interaction between intravenous fenretinide, ceftriaxone, and acetaminophen: a case report from a New Approaches to Neuroblastoma (NANT) Phase I study. BMC Res Notes 7:256|
|Solari, Valeria; Borriello, Lucia; Turcatel, Gianluca et al. (2014) MYCN-dependent expression of sulfatase-2 regulates neuroblastoma cell survival. Cancer Res 74:5999-6009|
|Sos, Martin L; Levin, Rebecca S; Gordan, John D et al. (2014) Oncogene mimicry as a mechanism of primary resistance to BRAF inhibitors. Cell Rep 8:1037-48|
|Marshall, Glenn M; Carter, Daniel R; Cheung, Belamy B et al. (2014) The prenatal origins of cancer. Nat Rev Cancer 14:277-89|
|Ilkanizadeh, Shirin; Lau, Jasmine; Huang, Miller et al. (2014) Glial progenitors as targets for transformation in glioma. Adv Cancer Res 121:1-65|
|Bergfeld, Scott A; Blavier, Laurence; DeClerck, Yves A (2014) Bone marrow-derived mesenchymal stromal cells promote survival and drug resistance in tumor cells. Mol Cancer Ther 13:962-75|
|Chen, Justin; Weiss, William A (2014) When deletions gain functions: commandeering epigenetic mechanisms. Cancer Cell 26:160-1|
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