The objective of the NANT Pre-Clinical Testing Lab is to facilitate the generation of hypothesis driven clinical trials within the NANT, and to provide guidance to NANT clinical investigators in prioritizing potential new therapeutics for phase I trials, and rational use of combinatorial therapy. The following Specific Aims will aid in achieving our objective: 1) Maintain a master cell bank of well-characterized human neuroblastoma cell lines. 2) Maintain DIMSCAN instrument in working order for use for experiments dealing with chemotherapeutic agents and IL-6, soluble IL-6, anti-IL-6 mAb CNTO 328, the STAT3 inhibitor stattic (Project 1), NK cells, anti-IGF1R mAb (Project 2), PI3K inhibitors, Aurora Kinase A type I and II inhibitors (Project 3), and drugs and drug combinations suggested by NANT investigators (Project 4). 3) Develop a """"""""microenvironment"""""""" model by co-culturing tumor cells with representative microenvironment cells (e.g., monocytes, mesenchymal cells) to test by DIMSCAN therapies targeting tumor cell - microenvironment cell interaction (e.g., anti-IL-6 mAb;lenalidomide) (collaboration with Projects 1 and 2). 4) Conduct in vitro cytotoxicity assays using DIMSCAN and provide assistance to project investigators in designing experiments, instructing in use of DIMSCAN and analyzing of data. 5) Assess anti-tumor activity of selected combinations using subcutaneous and disseminated disease xenograft models of multi-drug-resistant human neuroblastomas in immunocompromised mice by 1) determining maximal tolerated dose (MTD) of selected drug combinations;2) assessing pharmacodynamic evidence of drug activity at the MTD in tumor xenograft tissue;3) assessing the effect of the most active combinations on tumor growth delay and mouse survival.
Robust pre-clinical data generated through vigorous in vitro and in vivo testing will facilitate patient accrual to phase I trials, as patients most likely will enter trials with convincing experimental support. In addition, the pre-clinical modeling is crucial in establishing optimal scheduling for combination therapies, and synergistic and additive effects.
|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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