Abstract 5290: Imaging biomarkers of response to chemotherapy in neuroblastoma

Abstract

Abstract Neuroblastoma (NBL) is the most common extracranial solid tumor of childhood, accounting for between 7-10% of paediatric cancers. The proto-oncogene MYCN is amplified in 25% of NBL and is associated with high-risk disease, enhanced tumor angiogenesis and poor survival. A genetically-engineered mouse model for high risk, MYCN-amplified NBL has been generated by directing expression of MYCN to the peripheral neural crest of transgenic mice. As part of a multi-parametric MRI study, we have evaluated the native spin-lattice relaxation time T1, sensitive to the ratio of bound to free water in tissue, as a potential noninvasive biomarker of treatment response of TH-MYCN NBL to three different classes of anti-cancer agent. TH-MYCN mice with abdominal tumors were identified by palpation and imaged prior to and following treatment. Native T1 (ms) was quantified at 7T using an inversion recovery (IR)-trueFISP sequence. In control cohorts, tumor progression over 48 hours and 4 days was associated with no significant change in T1. A single 25mg/kg dose of cylophosphamide, the current standard of care for childhood NBL, caused a significant 54% reduction of tumor volume at 48 hours. Treatment of TH-MYCN NBL with CPM leads to extensive cell death, which occurs primarily through apoptosis, and this response was associated with a highly significant 15% reduction in native T1. Given the hypervascular nature of NBL, their response to anti-vascular therapies was also investigated. Treatment with the pan VEGF receptor inhibitor cediranib (6mg/kg daily over 2 days) resulted in significant 19% anti-tumor activity and 8% reduction in T1 at 48 hours. Furthermore, this response was associated with a significant reduction in uptake of the perfusion marker Hoechst 33342 compared to control, but no difference in necrosis. Treatment with a single 200mg/kg dose of the colchicine derivative ZD6126 resulted in significant and unprecedented 43% anti-tumor activity at 24 hours, and which was also associated with a significant 14% reduction in native T1. Histology revealed a significant reduction in Hoechst 33342 uptake and extensive tumor necrosis. Collectively, these data show a systematic reduction of native T1 in the TH-MYCN model with successful chemotherapy. The CPM and ZD6126-induced reduction in T1 is consistent with a histologically confirmed reduction in cell density and increased extravascular space following cytotoxic therapy. The reduction of T1 following treatment with cediranib may be attributable to the resolution of edema caused by reduced vascular permeability. Accurate quantification of T1 affords a generic noninvasive biomarker for chemotherapy-mediated cell death in the TH-MYCN model. The high sensitivity of T1 will accelerate the pre-clinical evaluation of novel therapeutics for childhood neuroblastoma in this model. Quantitation of native T1 could be easily incorporated into conventional imaging protocols used in clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5290. doi:10.1158/1538-7445.AM2011-5290