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.
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