Evaluation of Clinically Translatable MR Imaging Biomarkers of Therapeutic Response in the TH-MYCN Transgenic Mouse Model of Neuroblastoma
ABSTRACT Purpose:To evaluate noninvasive and clinically translatable magnetic resonance (MR) imaging biomarkers of therapeutic response in the TH-MYCN transgenic mouse model of aggressive, MYCN-amplified neuroblastoma.Materials and Methods:All experiments were performed in accordance with the local ethical review panel and the UK Home Office Animals Scientific Procedures Act 1986 and with the UK National Cancer Research Institute guidelines for the welfare of animals in cancer research. Multiparametric MR imaging was performed of abdominal tumors found in the TH-MYCN model. T2-weighted MR imaging, quantitation of native relaxation times T1 and T2, the relaxation rate R2*, and dynamic contrast-enhanced MR imaging were used to monitor tumor response to cyclophosphamide (25 mg/kg), the vascular disrupting agent ZD6126 (200 mg/kg), or the antiangiogenic agent cediranib (6 mg/kg, daily). Any significant changes in the measured parameters, and in the magnitude of the changes after treatment between treated and control cohorts, were identified by using Student two-tailed paired and unpaired t test, respectively, with a 5% level of significance.Results:Treatment with cyclophosphamide or cediranib induced a 54% or 20% reduction in tumor volume at 48 hours, respectively (P < .005 and P < .005, respectively; P < .005 and P < .005 versus control, respectively). Treatment with ZD6126 induced a 45% reduction in mean tumor volume 24 hours after treatment (P < .005; P < .005 versus control). The antitumor activity of cyclophosphamide, cediranib, and ZD6126 was consistently associated with a decrease in tumor T1 (P < .005, P < .005, and P < .005, respectively; P < .005, P < .005, and P < .005 versus control, respectively) and with a correlation between therapy-induced changes in native T1 and changes in tumor volume (r = 0.56; P < .005). Tumor response to cediranib was also associated with a decrease in the dynamic contrast-enhanced MR imaging-derived volume transfer constant (P = .07; P < .05 versus control) and enhancing fraction (P < .05; P < .01 versus control), and an increase in R2* (P < .005; P < .05 versus control).Conclusion:The T1 relaxation time is a robust noninvasive imaging biomarker of response to therapy in tumors in TH-MYCN mice, which emulate high-risk neuroblastoma in children. T1 measurements can be readily implemented on clinical MR systems and should be investigated in translational clinical trials of new targeted therapies for pediatric neuroblastoma.© RSNA, 2012Supplemental material:http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.12120128/-/DC1.
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- "In addition to ADC measurements, we also evaluated native T 1 and T 2 in WM266.4 tumours and observed no significant difference following selumetinib treatment. Native T 1 and T 2 are being actively investigated as putative pharmacodynamic biomarkers in oncology (McSheehy et al, 2010; Jamin et al, 2013). Our findings highlight the advantage of multiparametric MRI studies in assessing multiple imaging readouts in one experiment, thereby enabling the identification of the most robust biomarker of response, in this case tumour ADC. "
ABSTRACT: Background: Non-invasive imaging biomarkers underpin the development of molecularly targeted anti-cancer drugs. This study evaluates tumour apparent diffusion coefficient (ADC), measured by diffusion-weighted magnetic resonance imaging (DW-MRI), as a biomarker of response to the MEK1/2 inhibitor selumetinib (AZD6244, ARRY-142886) in human tumour xenografts. Methods: Nude mice bearing human BRAFV600D WM266.4 melanoma or BRAFV600E Colo205 colon carcinoma xenografts were treated for 4 days with vehicle or selumetinib. DW-MRI was performed before and 2 h after the last dose and excised tumours analysed for levels of phospho-ERK1/2, cleaved caspase 3 (CC3) and necrosis. Results: Selumetinib treatment induced tumour stasis and reduced ERK1/2 phosphorylation in both WM266.4 and Colo205 tumour xenografts. Relative to day 0, mean tumour ADC was unchanged in the control groups but was significantly increased by up to 1.6-fold in selumetinib-treated WM266.4 and Colo205 tumours. Histological analysis revealed a significant increase in necrosis in selumetinib-treated WM266.4 and Colo205 xenografts and CC3 staining in selumetinib-treated Colo205 tumours relative to controls. Conclusion: Changes in ADC following treatment with the MEK1/2 inhibitor selumetinib in responsive human tumour xenografts were concomitant with induction of tumour cell death. ADC may provide a useful non-invasive pharmacodynamic biomarker for early clinical assessment of response to selumetinib and other MEK-ERK1/2 signalling-targeted therapies.British Journal of Cancer 08/2013; 109(6). DOI:10.1038/bjc.2013.456 · 4.82 Impact Factor
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ABSTRACT: Laser-induced interstitial thermal therapy (LITT) has recently emerged as a new, less invasive alternative to craniotomy for treating epilepsy; which allows for focussed delivery of laser energy monitored in real time by MRI, for precise removal of the epileptogenic foci. Despite being minimally invasive, the effects of laser ablation on the epileptogenic foci (reflected by changes in MR imaging markers post-LITT) are currently unknown. In this work, we present a quantitative framework for evaluating LITT-related changes by quantifying per-voxel changes in MR imaging markers which may be more reflective of local treatment related changes (TRC) that occur post-LITT, as compared to the standard volumetric analysis which involves monitoring a more global volume change across pre-, and post-LITT MRI. Our framework focuses on three objectives: (a) development of temporal MRI signatures that characterize TRC corresponding to patients with seizure freedom by comparing differences in MR imaging markers and monitoring them over time, (b) identification of the optimal time point when early LITT induced effects (such as edema and mass effect) subside by monitoring TRC at subsequent time-points post-LITT, and (c) identification of contributions of individual MRI protocols towards characterizing LITT-TRC for epilepsy by identifying MR markers that change most dramatically over time and employ individual contributions to create a more optimal weighted MP-MRI temporal profile that can better characterize TRC compared to any individual imaging marker. A cohort of patients were monitored at different time points post-LITT via MP-MRI involving T1-w, T2-w, T2-GRE, T2-FLAIR, and apparent diffusion coefficient (ADC) protocols. Post affine registration of individual MRI protocols to a reference MRI protocol pre-LITT, differences in individual MR markers are computed on a per-voxel basis, at different time-points with respect to baseline (pre-LITT) MRI as well as across subsequent time-points. A time-dependent MRI profile corresponding to successful (seizure-free) is then created that captures changes in individual MR imaging markers over time. Our preliminary analysis on two patient studies suggests that (a) LITT related changes (attributed to swelling and edema) appear to subside within 4-weeks post-LITT, (b) ADC may be more sensitive for evaluating early TRC (up to 3-months), and T1-w may be more sensitive in evaluating early delayed TRC (1-month, 3-months), while T2-w and T2-FLAIR appeared to be more sensitive in identifying late TRC (around 6-months post-LITT) compared to the other MRI protocols under evaluation. T2-GRE was found to be only nominally sensitive in identifying TRC at any follow-up time-point post-LITT. The framework presented in this work thus serves as an important precursor to a comprehensive treatment evaluation framework that can be used to identify sensitive MR markers corresponding to patient response (seizure-freedom or seizure recurrence), with an ultimate objective of making prognostic predictions about patient outcome post-LITT.Proceedings of SPIE - The International Society for Optical Engineering 03/2013; 8671. DOI:10.1117/12.2008157 · 0.20 Impact Factor
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ABSTRACT: We determined whether contrast-enhanced computed tomography (CECT) attenuation obtained using a µCT scanner correlated with the glycosaminoglycan (GAG) content and distribution in ex vivo bovine menisci. Bovine samples were immersed in different concentrations of the contrast agents CA4+ and Ioxaglate, and the µCT images were compared to Safranin-O staining. CA4+ and Ioxaglate diffusion-in kinetics and the correlation between their CECT attenuations and GAG content were investigated. CA4+ and Ioxaglate both reached steady state in the meniscal regions within 95 h, with tau values of 20.6 ± 3.98 and 25.9 ± 3.71 h (mean ± SD), respectively. Both agents diffused preferentially through the proximal and secondarily through the distal surface. The CA4+ CECT attenuation was strongly and positively correlated with the GAG content of the meniscus regions (R(2) = 0.89, p < 0.001) at low concentrations (12 mgI/ml), while the Ioxaglate CECT attenuation was moderately and negatively correlated with the GAG content (R(2) = 0.51, p = 0.03) at 60 mgI/ml. CECT can image ex vivo menisci, and the CA4+, compared to Ioxaglate, enhanced attenuation strongly correlates with the GAG content and distribution in bovine meniscus. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.Journal of Orthopaedic Research 07/2013; 31(11). DOI:10.1002/jor.22421 · 2.97 Impact Factor