Abstract 1559: Evaluation of MR imaging biomarkers of the vascular and infiltrative phenotype in intracranial MDA-MB-231 tumors.
Authors: Boult Jessica KR , Jury Alexa , Popov Sergey , Perryman Lara , Box Gary , Jones Chris , Eccles Suzanne A. , Robinson Simon P. 
Published: August 2014

Tumors growing in the brain often invade into the parenchyma and co-opt the existing vasculature leaving the blood brain barrier (BBB) intact; extravasation of the Gd-DTPA contrast agent used in MRI is therefore precluded. Anti-angiogenic agents can restore the compromised BBB of neovascular regions resulting in ‘pseudoresponse’ in human glioblastoma (GBM), and preclinical brain metastasis models. Non-invasive imaging strategies are required to accurately interrogate brain specific growth patterns. Preclinical models that faithfully emulate infiltrative gliomas are limited. Intracranial implantation of MDA-MB-231 breast cancer cells results in tumors exhibiting substantial local invasion, principally occurring along existing blood vessels. Multiparametric MRI was used to identifying sensitive biomarkers of infiltrative tumor growth in this model. Alteration in the vascular phenotype was assessed in response to pan-VEGFR inhibitor cediranib or cross reactive human/mouse anti-VEGF-A antibody B20-4.1.1.

Intracranial MDA-MB-231 tumors were heterogeneous; areas of high apparent diffusion coefficient (ADC, mm2s−1), a biomarker of cellularity, correlated with the most hyperintense regions on T2-weighted images and areas of histologically confirmed edema. Regions of high Gd-DTPA extravasation were distinct from the areas of high ADC, but correlated with regions of high fractional blood volume (fBV) detected using intravascular USPIO particles. Infiltrative regions identified on H&E images corresponded to areas of limited Gd-DTPA leakage and low fBV.

Cediranib (3 x 6mg/kg) caused significant tumor growth delay after 48h compared to controls (cediranib 160 ± 9% pre-treatment volume, vehicle 210 ± 14%, p&lt;0.05, unpaired t-test). A 50% reduction in Ktrans (min−1), a compound biomarker of permeability/perfusion, was observed following cediranib treatment (p&lt;0.05, paired t-test). Perfused tumor area, assessed using Hoechst 33342, was lower in treated tumors (cediranib 5.4 ± 0.6%, vehicle 9.1 ± 1.5%, p&lt;0.05), confirming reduced vascular function. Cediranib also led to a 9% reduction in tumor ADC (p&lt;0.05), possibly due to resolution of edema, as observed in GBM patients.

A single 10mg/kg dose of B20-4.1.1 resulted in significant tumor growth delay over 48h (B20-4.1.1 120 ± 18%, control antibody 230 ± 8%) and a 58% reduction in Ktrans (p&lt;0.05), but no change in ADC was observed.

BBB integrity following treatment is being evaluated to inform on the contributions of its restoration, and altered vascular function, to the observed changes in vascular imaging biomarkers.

Intracranial MDA-MB-231 tumors provide a useful model for the development of imaging biomarkers of the infiltrative and vascular phenotype of tumors in the brain, which are essential for the assessment of the novel invasive orthotopic glioma models currently being developed, and their response to therapeutics.

Citation Format: Jessica KR Boult, Alexa Jury, Sergey Popov, Lara Perryman, Gary Box, Chris Jones, Suzanne A. Eccles, Simon P. Robinson. Evaluation of MR imaging biomarkers of the vascular and infiltrative phenotype in intracranial MDA-MB-231 tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1559. doi:10.1158/1538-7445.AM2013-1559