Abstract 4189: Characterization of tumor progression and chemoresponse in a novel transgenic mouse model of neuroblastoma (TH-MYCN) using magnetic resonance imaging

Abstract

Abstract Neuroblastoma is the most common extracranial childhood solid tumour, accounting for between 7-10% of paediatric cancers, and originates in peripheral nerve tissues. The proto-oncogene MYCN is amplified in 25% of high-risk neuroblastoma and is associated with an aggressive tumour phenotype, enhanced tumour angiogenesis and poor clinical prognosis. The Mycn oncoprotein is highly expressed in tumour but not in normal tissues, making it an attractive candidate for targeted therapeutics. To assess the relevance of MYCN overexpression in neuroblastoma, and to test Mycn-targeted therapeutics, a murine transgenic model that faithfully replicates the disease biology of high-risk neuroblastoma by targeting overexpression of MYCN to the neural crest was constructed. As a prelude to the assessment of novel therapeutics for the treatment of neuroblastoma, and given the retroperitoneal localisation of these tumours, the TH-MYCN model has been characterised in vivo by non-invasive MRI. Mice with abdominal tumours identified by palpation were imaged on a 7T Bruker MicroImaging system (n=7). Anatomical T2-weighted coronal images revealed that all TH-MYCN mice developed large peri-renal retroperitoneal tumours, likely originating from the adrenal glands, that displaced major abdominal organs (kidney, liver, stomach). Major vessels were characteristically distorted, with enlargement of the abdominal aorta and vena cava. Forty-eight hours after treatment with cyclophosphamide (100mg/kg x 2 doses, over 48 hours), tumours were difficult to identify or were undetectable, consistent with previous studies showing remission in TH-MYCN and with the clinical sensitivity of childhood neuroblastoma to CP. Further screening of these mice by MRI is ongoing to interrogate tumour relapse. Additionally, quantitation of tumour MRI relaxation rates revealed a very heterogeneous spatial distribution of T1 (1748 ± 14ms), T2 (55 ± 1ms) and R2* (115 ± 3s−1). The relatively fast baseline R2* is indicative of a large tumour blood volume, confirmed by the intense red coloration of these tumours at excision, and the presence of a large proportion of blood lakes observed histologically. The high degree of tumour perfusion was corroborated by dynamic contrast-enhanced MRI following intravenous injection of Gd-DTPA, and which revealed parenchymal enhancement typically across the whole tumour (IAUGC60 = 0.13 ± 0.01ms). This study reinforces the TH-MYCN murine model as a faithful representation of human neuroblastoma in its anatomical and radiological appearance, and in its high sensitivity to CP. It also demonstrates that the implementation of MRI screening is an asset in the development of novel therapeutics for neuroblastoma and could accelerate their clinical development by allowing simultaneous evaluation of MRI biomarkers of treatment response. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4189.