Abstract A05: A novel minimal residual disease model of neuroblastoma in mice
Authors: Jackson Jeremy R. , Kim Youngleem , Seeger Robert C. , Kim Eugene S. 
Published: May 2016

Introduction: Despite aggressive medical and surgical therapy, the 5-year survival rate for high-risk neuroblastoma remains poor at 40-50%. The vast majority of these deaths are not due to the primary tumor but from recurrent metastatic disease. However, current in vivo models of neuroblastoma primarily study the efficacy of novel treatments on primary tumor growth (subcutaneous, orthotopic, transgenic) as opposed to residual metastatic disease as seen in patients. We sought to create an in vivo model of minimal residual disease (MRD), which clinically replicates tumor recurrence and metastasis after surgical resection.

Methods: We surgically injected one million luciferase expressing human neuroblastoma cells into the left renal capsule of NSG mice to establish tumor xenografts. The neuroblastoma cell lines CHLA-255 (n=10) and CHLA-136 (n=8) were utilized. At day 14, half of CHLA-255 mice (n=5) and CHLA-136 mice (n=4) underwent complete resection of their primary tumors, while the remaining mice underwent a sham surgery. Extent of disease in mice was monitored weekly by bioluminescent imaging. Mice were sacrificed when they met institutional criteria for euthanasia (weakness/paralysis, seizures, inability to eat or drink, moribund state, dyspnea). Survival data was analyzed using Kaplan-Meier method with significance being determined by log-rank test. P&lt;0.05 was considered significant.

Results: In the CHLA-255 group, at the time of sacrifice, 5/5 control mice and 1/5 resection mice were found to have discrete tumors in the left kidney bed. By imaging, 4/5 control mice and 5/5 resected mice were found to have evidence of metastatic disease (femur, liver, brain) at the time of sacrifice. The tumor resection cohort had a mean survival of 47.4 ± 1.3 days compared to 33.8 ± 4.1 days for the non-resection cohort (p=0.003).

In the CHLA-136 group, 4/4 control mice and 4/4 resection mice had discrete tumors in the left kidney bed at the time of sacrifice. Imaging demonstrated that 2/4 control mice and 4/4 resected mice were found to have evidence of metastatic disease at the time of sacrifice. The tumor resection cohort had a mean survival of 44 ± 3.2 days compared to 36 ± 2.7 days for the non-resection cohort (p=0.007).

Conclusion: In this study, we describe a novel neuroblastoma model of minimal residual disease in mice. Following the resection of an orthotopic xenograft tumor, our in vivo model of MRD demonstrates a 100% rate of metastatic disease in two cell lines of neuroblastoma. This MRD model serves as an innovative means to test novel therapies as well as elucidate the mechanisms in metastatic disease in neuroblastoma.

Citation Format: Jeremy R. Jackson, Youngleem Kim, Robert C. Seeger, Eugene S. Kim. A novel minimal residual disease model of neuroblastoma in mice. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr A05.