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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Type
Research Program Projects (P01)
Project #
5P01CA081403-15
Application #
8677720
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
Budget End
Support Year
15
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Children's Hospital of Los Angeles
Department
Type
DUNS #
City
Los Angeles
State
CA
Country
United States
Zip Code
94143
DuBois, Steven G; Marachelian, Araz; Fox, Elizabeth et al. (2016) Phase I Study of the Aurora A Kinase Inhibitor Alisertib in Combination With Irinotecan and Temozolomide for Patients With Relapsed or Refractory Neuroblastoma: A NANT (New Approaches to Neuroblastoma Therapy) Trial. J Clin Oncol 34:1368-75
Trieu, Megan; DuBois, Steven G; Pon, Elizabeth et al. (2016) Impact of Whole-Body Radiation Dose on Response and Toxicity in Patients With Neuroblastoma After Therapy With 131 I-Metaiodobenzylguanidine (MIBG). Pediatr Blood Cancer 63:436-42
DuBois, Steven G; Groshen, Susan; Park, Julie R et al. (2015) Phase I Study of Vorinostat as a Radiation Sensitizer with 131I-Metaiodobenzylguanidine (131I-MIBG) for Patients with Relapsed or Refractory Neuroblastoma. Clin Cancer Res 21:2715-21
Chen, Justin; Hackett, Christopher S; Zhang, Shile et al. (2015) The genetics of splicing in neuroblastoma. Cancer Discov 5:380-95
Yanik, Gregory A; Villablanca, Judith G; Maris, John M et al. (2015) 131I-metaiodobenzylguanidine with intensive chemotherapy and autologous stem cell transplantation for high-risk neuroblastoma. A new approaches to neuroblastoma therapy (NANT) phase II study. Biol Blood Marrow Transplant 21:673-81
HaDuong, Josephine H; Blavier, Laurence; Baniwal, Sanjeev K et al. (2015) Interaction between bone marrow stromal cells and neuroblastoma cells leads to a VEGFA-mediated osteoblastogenesis. Int J Cancer 137:797-809
Wang, L L; Teshiba, R; Ikegaki, N et al. (2015) Augmented expression of MYC and/or MYCN protein defines highly aggressive MYC-driven neuroblastoma: a Children's Oncology Group study. Br J Cancer 113:57-63
DuBois, S G; Allen, S; Bent, M et al. (2015) Phase I/II study of (131)I-MIBG with vincristine and 5 days of irinotecan for advanced neuroblastoma. Br J Cancer 112:644-9
Cage, Tene Aneka; Chanthery, Yvan; Chesler, Louis et al. (2015) Downregulation of MYCN through PI3K Inhibition in Mouse Models of Pediatric Neural Cancer. Front Oncol 5:111
Huang, Shih-ying; Bolch, Wesley E; Lee, Choonsik et al. (2015) Patient-specific dosimetry using pretherapy [¹²⁴I]m-iodobenzylguanidine ([¹²⁴I]mIBG) dynamic PET/CT imaging before [¹³¹I]mIBG targeted radionuclide therapy for neuroblastoma. Mol Imaging Biol 17:284-94

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