The tumor microenvironment is considered to be an important factor in tumorigenesis and tumor progression and metastasis. In view of the fact that 70% of patients with stage 4 and stage 4s neuroblastoma have metastatic disease in the bone marrow and 56% in the bone at the time of diagnosis, our project has been focused on the study of the bone marrow microenvironment in neuroblastoma progression. Over the last 5 years, we have identified a pathway at the center of the interactions between neuroblastoma cells and bone marrow-derived mesenchymal cells (BMDMCs). We observed that neuroblastoma cells in the bone marrow microenvironment produce Galectin-3 binding protein (Gal-3BP) that interacts with Galectin 3 present in BMDMCs and stimulates the production of Interleukin-6 (IL-6) by these cells. IL-6 has multiple effects in the bone marrow. It stimulates osteoclasts, enhances neuroblastoma cell proliferation and protects them from drug-induced apoptosis. Furthermore, in collaboration with project 2, we have shown that th Gal-3BP/Gal- 3/IL-6 pathway also controls the interaction between neuroblastoma cells and monocytes that infiltrate primary tumors. On the basis of these data, we hypothesize that the bone marrow provides tumor cells with a sanctuary against the cytotoxic effects of chemotherapy via a Gal-3 BP/Gal-3/IL-6 pathway. Consequently, we hypothesize that targeting this pathway would be of therapeutic benefit in patients with neuroblastoma and bone marrow and bone metastasis. This project has 3 specific aims:
Aim 1, will examine the mechanism by which Gal-3BP stimulates the transcriptional expression of IL-6 in BMDMCs.
Aim 2 will examine the mechanism by which IL-6 protects tumor cells from drug toxicity with a particular focus on the role of anti-apoptotic proteins like survivin, XIAP, Bcl-2 and Bcl-{XL} that are upregulated by IL-6 in neuroblastoma cells and on signaling pathways (STAT-3, ERK1/2 and Akt) downstream of IL-6 signaling.
In aim 3, in collaboration with project 2, 3 and 4, we will examine the effect of genetic ablation of IL-6 on neuroblastoma initiation and progression and the effect of targeting the Gal-3BP/Gal-3/IL-6 pathway on neuroblastoma progression in preclinical models. The focus of this project is therefore on the understanding of the molecular mechanisms that control the interaction between neuroblastoma cells and the bone marrow microenvironment and on using this information to identify large and small molecules that can be tested in preclinical trials by our project and in clinical trials by project 4 and the NANT.

Public Health Relevance

The bone marrow provides a sanctuary for tumor cells and is a frequent site of metastasis in neuroblastoma. The goals of this project are 1. to acquire a fundamental understanding of how the interactions between neuroblastoma cells and the bone marrow microenvironment contribute to cancer progression, 2. to rapidly use this knowledge to test in preclinical models agents interfering with these interactions, and 3. to identify those agents that are the most likely to be of therapeutic benefit in 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 #
8506983
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
$309,938
Indirect Cost
$172,530
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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