Neuroblastoma, a tumor arising from embryonic neural crest, is the most common extra-cranial solid tumor of childhood, and less than 40% of children with high-risk features survive despite intensive treatment. Hypothesis: New tumor-targeted therapies that are non-cross resistant with standard chemotherapy and have been validated in pre-clinical studies will induce responses in patients with refractory tumors and improve outcome.
Specific Aims : 1) To establish the tolerability and efficacy of [131]l-MIBG (targeting the norepinephrine transporter) with hematopoietic stem cell support when combined with chemotherapy, novel biologies, and/or radiosensitizers with combinatorial pre-clinical activity against resistant neuroblastoma; 2) Define rational combinations of agents that target key molecules relevant to tumor pathways and/or to tumor-microenvironment interactions that may be combined with standard cytotoxic agents to maximize efficacy against neuroblastoma, with pharmacokinetic and pharmacodynamic validation at the MTD; 3) Develop biomarker and semi-quantitative imaging technologies that provide additional neuroblastomaspecific endpoints to evaluate response to therapies. Methods and Interactions: We will focus on combination therapy that has specific rationale for neuroblastoma, utilizing Phase I data for single agents tested against a broader spectrum of solid tumors in combination with laboratory data from Projects 1-3 and Pre-Clinical Testing Core D. Examples of agents to be tested include MlBG with radiosensitizers and chemotherapy, anti-IL6 with metronomic cyclophosphamide and zometa (Project 1), immunotherapy (Project 2), PIS kinase inhibitors (Project 3). NANT (New Approaches to Neuroblastoma Therapy), is our consortium of 15 institutions that will conduct the clinical trials with the support of the cores for administrative research support, histopathology, pre-clinical testing, biostatistics, as well as the NANT Operations Center. The NANT works in very close cooperation with the Children's Oncology Group (COG), CTEP and the FDA, and industry sponsors with the goal of bringing the most promising agents from our Phase I trials forward into Phase II and then national Phase III trials.

Public Health Relevance

These studies, incorporating dosimetry, pharmacokinetics, pharmacodynamics and validation of new response measures, will identify promising agents and regimens derived from the PPG Projects 1-3 that are non-cross resistant with current treatments and will result in improved survival for children with high-risk neuroblastoma.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA081403-14
Application #
8506986
Study Section
Special Emphasis Panel (ZCA1-GRB-S)
Project Start
Project End
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
14
Fiscal Year
2013
Total Cost
$213,697
Indirect Cost
$43,132
Name
Children's Hospital of Los Angeles
Department
Type
DUNS #
052277936
City
Los Angeles
State
CA
Country
United States
Zip Code
90027
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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