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.
|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 [Â¹Â²â´I]m-iodobenzylguanidine ([Â¹Â²â´I]mIBG) dynamic PET/CT imaging before [Â¹Â³Â¹I]mIBG targeted radionuclide therapy for neuroblastoma. Mol Imaging Biol 17:284-94|
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