Neuroblastoma is the most common extra cranial solid tumor of childhood, and 45% of patients have aggressive tumors, nearly all of which are metastatic (stage 4) when diagnosed. Over the past 20 years, long-term survival has steadily improved to 40% with increasing intensity of non-specific cytotoxic induction and consolidation therapy and with biotherapy of minimal residual disease after consolidation. Even though long-term survival has improved, the limit of host tolerance for non-specific cytotoxic therapy has been reached. We hypothesize that improved survival for newly diagnosed patients as well as for established patients with refractory or recurrent disease will result from new combinatorial therapies that target critical pathways of tumor and host cells that promote neuroblastoma growth and survival in primary and metastatic sites. Thus, the unifying theme of this PPG is to integrate biology and developmental therapeutics research with early phase clinical trials with the overall goal of improving survival for children with high-risk neuroblastoma.
Our Specific Aims are as follows: 1) Perform biologic research to identify and further understand molecules and pathways of tumor and microenvironment cells that are responsible for neuroblastoma growth. 2) Perform pre-clinical therapeutic research with drugs and biologics to develop effective strategies against neuroblastoma. 3) Perform early phase clinical trials of combinatorial strategies targeting molecules and pathways of tumor and microenvironment cells to determine appropriate dose and schedule, pharmacology and pharmacodynamics, and, within the context of such trials, anti-tumor activity. Project 1: The bone marrow microenvironment is investigated with emphasis on the role of IL-6 and STAT3 activation in bone marrow and bone metastasis and on identifying effective drugs and biologics that target this pathway. Project 2: Immunotherapy strategies focus on natural killer (NK) cells. Studies maximize NK activity with tumor cell targeting antibodies and with agents that modify the tumor microenvironment milieu to minimize NK suppressive effects of monocytes/macrophages producing IL-6 and TGF?1. Project 3: Small molecules, including PI3K, PI3K+mT0R, and Aurora Kinase A inhibitors that result in destabilization and degradation [sic] the MYCN protein, are investigated for their anti-tumor cell activity as well as their effects upon microenvironment cells. Project 4: New strategies developed in our laboratories are tested in phase I and II trials by the New Approaches to Neuroblastoma Therapy (NANT) consortium (www.nant.org), which includes 15 pediatric oncology institutions across the US and in Canada.
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|Borriello, Lucia; Nakata, Rie; Sheard, Michael A et al. (2017) Cancer-Associated Fibroblasts Share Characteristics and Protumorigenic Activity with Mesenchymal Stromal Cells. Cancer Res 77:5142-5157|
|Erdreich-Epstein, Anat; Singh, Alok R; Joshi, Shweta et al. (2017) Association of high microvessel ?v?3 and low PTEN with poor outcome in stage 3 neuroblastoma: rationale for using first in class dual PI3K/BRD4 inhibitor, SF1126. Oncotarget 8:52193-52210|
|Tran, Hung C; Wan, Zesheng; Sheard, Michael A et al. (2017) TGF?R1 Blockade with Galunisertib (LY2157299) Enhances Anti-Neuroblastoma Activity of the Anti-GD2 Antibody Dinutuximab (ch14.18) with Natural Killer Cells. Clin Cancer Res 23:804-813|
|Villablanca, Judith G; Volchenboum, Samuel L; Cho, Hwangeui et al. (2016) A Phase I New Approaches to Neuroblastoma Therapy Study of Buthionine Sulfoximine and Melphalan With Autologous Stem Cells for Recurrent/Refractory High-Risk Neuroblastoma. Pediatr Blood Cancer 63:1349-56|
|Vaughan, Lynsey; Clarke, Paul A; Barker, Karen et al. (2016) Inhibition of mTOR-kinase destabilizes MYCN and is a potential therapy for MYCN-dependent tumors. Oncotarget 7:57525-57544|
|Borriello, Lucia; Seeger, Robert C; Asgharzadeh, Shahab et al. (2016) More than the genes, the tumor microenvironment in neuroblastoma. Cancer Lett 380:304-14|
|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|
|Challagundla, Kishore B; Wise, Petra M; Neviani, Paolo et al. (2015) Exosome-mediated transfer of microRNAs within the tumor microenvironment and neuroblastoma resistance to chemotherapy. J Natl Cancer Inst 107:|
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