Evaluation of Clinically Translatable MR Imaging Biomarkers of Therapeutic Response in the TH-MYCN Transgenic Mouse Model of Neuroblastoma

The Royal Marsden NHS Foundation Trust, Londinium, England, United Kingdom
Radiology (Impact Factor: 6.87). 11/2012; 266(1). DOI: 10.1148/radiol.12120128
Source: PubMed


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.

Download full-text


Available from: Yann Jamin, Nov 05, 2015
  • Source
    • "All the Th-ALKF1174L/Th-MYCN (n = 23) and Th-MYCN (n = 21) mice examined presented with abdominal tumors with wide range of volumes (525–3400 mm3 for tumors in Th-ALKF1174L/Th-MYCN mice and 335–2450 mm3 for tumors in Th-MYCN mice). Tumors in the Th-MYCN mice appeared heterogeneous, with 94% of tumors presenting with areas of hypointense signal, consistent with previous observations [8]. Tumors in the Th-ALKF1174L/Th-MYCN mice were generally hyperintense and significantly more homogeneous, with only 48% of the tumors having hypointense regions (p = 0.006, χ2-test). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The early identification of children presenting ALKF1174L-mutated neuroblastoma, which are associated with resistance to the promising ALK inhibitor crizotinib and a marked poorer prognosis, has become a clinical priority. In comparing the radiology of the novel Th-ALKF1174L/Th-MYCN and the well-established Th-MYCN genetically-engineered murine models of neuroblastoma using MRI, we have identified a marked ALKF1174L-driven vascular phenotype. We demonstrate that quantitation of the transverse relaxation rate R2* (s-1) using intrinsic susceptibility-MRI under baseline conditions and during hyperoxia, can robustly discriminate this differential vascular phenotype, and identify MYCN-driven tumors harboring the ALKF1174L mutation with high specificity and selectivity. Intrinsic susceptibility-MRI could thus potentially provide a non-invasive and clinically-exploitable method to help identifying children with MYCN-driven neuroblastoma harboring the ALKF1174L mutation at the time of diagnosis.
    PLoS ONE 03/2014; 9(3):e92886. DOI:10.1371/journal.pone.0092886 · 3.23 Impact Factor
  • Source
    • "Everolimus also decreased levels of total choline (Cho) in RIF-1 tumours, which is another marker of viable and proliferating cells, in this case reflecting membrane turnover. Cho tends to be higher in tumour than normal tissue [33] and successful chemotherapy has also been shown to decrease in Cho in both experimental models [7,8,10] and the clinic [34,35]. In the RIF-1 tumours, these proliferation markers correlated significantly with each other as well as with the ΔT1, supporting the notion that ΔT1 is a surrogate of the remaining number of proliferating cells in a tumour after therapy even though our histological analysis suggests that it cannot be measuring cell number or density directly. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Effective chemotherapy rapidly reduces the spin-lattice relaxation of water protons (T1) in solid tumours and this change (DeltaT1) often precedes and strongly correlates with the eventual change in tumour volume (TVol). To understand the biological nature of DeltaT1, we have performed studies in vivo and ex vivo with the allosteric mTOR inhibitor, everolimus. Mice bearing RIF-1 tumours were studied by magnetic resonance imaging (MRI) to determine TVol and T1, and MR spectroscopy (MRS) to determine levels of the proliferation marker choline and levels of lipid apoptosis markers, prior to and 5 days (endpoint) after daily treatment with vehicle or everolimus (10 mg/kg). At the endpoint, tumours were ablated and an entire section analysed for cellular and necrotic quantification and staining for the proliferation antigen Ki67 and cleaved-caspase-3 as a measure of apoptosis. The number of blood-vessels (BV) was evaluated by CD31 staining. Mice bearing B16/BL6 melanoma tumours were studied by MRI to determine T1 under similar everolimus treatment. At the endpoint, cell bioluminescence of the tumours was measured ex vivo. Everolimus blocked RIF-1 tumour growth and significantly reduced tumour T1 and total choline (Cho) levels, and increased polyunsaturated fatty-acids which are markers of apoptosis. Immunohistochemistry showed that everolimus reduced the%Ki67+ cells but did not affect caspase-3 apoptosis, necrosis, BV-number or cell density. The change in T1 (DeltaT1) correlated strongly with the changes in TVol and Cho and%Ki67+. In B16/BL6 tumours, everolimus also decreased T1 and this correlated with cell bioluminescence; another marker of cell viability. Receiver-operating-characteristic curves (ROC) for everolimus on RIF-1 tumours showed that DeltaT1 had very high levels of sensitivity and specificity (ROCAUC = 0.84) and this was confirmed for the cytotoxic patupilone in the same tumour model (ROCAUC = 0.97). These studies suggest that DeltaT1 is not a measure of cell density but reflects the decreased number of remaining viable and proliferating tumour cells due to perhaps cell and tissue destruction releasing proteins and/or metals that cause T1 relaxation. DeltaT1 is a highly sensitive and specific predictor of response. This MRI method provides the opportunity to stratify a patient population during tumour therapy in the clinic.
    BMC Cancer 02/2014; 14(1):88. DOI:10.1186/1471-2407-14-88 · 3.36 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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 · 4.84 Impact Factor
Show more