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 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.
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.
|Pinto, Navin; DuBois, Steven G; Marachelian, Araz et al. (2018) Phase I study of vorinostat in combination with isotretinoin in patients with refractory/recurrent neuroblastoma: A new approaches to Neuroblastoma Therapy (NANT) trial. Pediatr Blood Cancer 65:e27023|
|DuBois, Steven G; Mosse, Yael P; Fox, Elizabeth et al. (2018) Phase II Trial of Alisertib in Combination with Irinotecan and Temozolomide for Patients with Relapsed or Refractory Neuroblastoma. Clin Cancer Res 24:6142-6149|
|Villablanca, Judith G; Ji, Lingyun; Shapira-Lewinson, Adi et al. (2018) Predictors of response, progression-free survival, and overall survival using NANT Response Criteria (v1.0) in relapsed and refractory high-risk neuroblastoma. Pediatr Blood Cancer 65:e26940|
|Niemas-Teshiba, Risa; Matsuno, Ryosuke; Wang, Larry L et al. (2018) MYC-family protein overexpression and prominent nucleolar formation represent prognostic indicators and potential therapeutic targets for aggressive high-MKI neuroblastomas: a report from the children's oncology group. Oncotarget 9:6416-6432|
|Webb, Matthew W; Sun, Jianping; Sheard, Michael A et al. (2018) Colony stimulating factor 1 receptor blockade improves the efficacy of chemotherapy against human neuroblastoma in the absence of T lymphocytes. Int J Cancer 143:1483-1493|
|Cho, Hwang Eui; Min, H Kang (2017) Analysis of fenretinide and its metabolites in human plasma by liquid chromatography-tandem mass spectrometry and its application to clinical pharmacokinetics. J Pharm Biomed Anal 132:117-124|
|Zheng, Tina; Ménard, Marie; Weiss, William A (2017) Neuroblastoma Metastases: Leveraging the Avian Neural Crest. Cancer Cell 32:395-397|
|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|
|Marachelian, Araz; Villablanca, Judith G; Liu, Cathy W et al. (2017) Expression of Five Neuroblastoma Genes in Bone Marrow or Blood of Patients with Relapsed/Refractory Neuroblastoma Provides a New Biomarker for Disease and Prognosis. Clin Cancer Res 23:5374-5383|
|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|
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