Malignant gliomas present great difficulties in treatment, with little change over the past 25 years in the median survival time of 12 months. Current treatment options include surgery, radiotherapy (RT), and chemotherapy. New therapies aimed at suppressing the formation of new vasculature (antiangiogenic treatments), or destroying formed tumor vasculature (vascular disrupting agents) show promise. This application will use magnetic resonance (MR) contrast agents (CAs) and MR detection to measure blood volume, the blood-to-brain transvascular transfer constant, the extravascular extracellular space, and the total extracellular space in cerebral tumors, and also to measure tumor blood flow using MR arterial spin tagging. These parameters present an important summary of the physiology of vasculature, both normal and tumorous. It is proposed to use these vascular parameters as MR biomarkers in animal models of cerebral gliomas. In a series of experiments, we will examine the change in MR-measured vascular parameters after antiangiogenic therapy, after vascular disrupting agent, and after RT, with all MR measures correlated with histopathological assessments of vascular and cellular density in the model tumors. After single-agent therapies are studied, combination therapies will be studied, and MRI vascular biomarkers will be examined as predictors of response as judged both by histopathological assessments and long-term survival. At the completion of these studies, the relation of MR-measured vascular parameters to cellular responses to single and combination therapies will be established, and the utility of MR-measured vascular parameters as predictors of long-term survival assessed. The MR-measured parameters can be translated to clinical use and evaluated as predictors of human tumor response to therapies. These studies represent a first step in a paradigm shift in cancer treatment delivery from a heuristic and formulaic approach to an individualized plan of image guided treatment and response monitoring.
The utility of quantitative MR-measured vascular parameters for predicting brain tumor response to promising anti-angiogenic agents and vascular disrupting agents applied singly or in combination with or without radiation therapy will be shown. The studies presented represent a first step in a paradigm shift in cancer treatment delivery from a one-solution-fits-all approach to an individualized plan of image guided treatment and response monitoring.
|Chwang, Wilson B; Jain, Rajan; Bagher-Ebadian, Hassan et al. (2014) Measurement of rat brain tumor kinetics using an intravascular MR contrast agent and DCE-MRI nested model selection. J Magn Reson Imaging 40:1223-9|
|Aryal, Madhava P; Nagaraja, Tavarekere N; Brown, Stephen L et al. (2014) Intratumor distribution and test-retest comparisons of physiological parameters quantified by dynamic contrast-enhanced MRI in rat U251 glioma. NMR Biomed 27:1230-8|
|Aryal, Madhava P; Nagaraja, Tavarekere N; Keenan, Kelly A et al. (2014) Dynamic contrast enhanced MRI parameters and tumor cellularity in a rat model of cerebral glioma at 7 T. Magn Reson Med 71:2206-14|
|Ewing, James R; Bagher-Ebadian, Hassan (2013) Model selection in measures of vascular parameters using dynamic contrast-enhanced MRI: experimental and clinical applications. NMR Biomed 26:1028-41|
|Knight, Robert A; Nagaraja, Tavarekere N; Ewing, James R (2011) Letter by Knight et al regarding article, "Validation of in vivo magnetic resonance imaging blood-brain barrier permeability measurements by comparison with gold standard histology". Stroke 42:e568|
|Nagaraja, Tavarekere N; Ewing, James R; Karki, Kishor et al. (2011) MRI and quantitative autoradiographic studies following bolus injections of unlabeled and (14)C-labeled gadolinium-diethylenetriaminepentaacetic acid in a rat model of stroke yield similar distribution volumes and blood-to-brain influx rate constants. NMR Biomed 24:547-58|
|Paudyal, Ramesh; Bagher-Ebadian, Hassan; Nagaraja, Tavarekere N et al. (2011) Modeling of Look-Locker estimates of the magnetic resonance imaging estimate of longitudinal relaxation rate in tissue after contrast administration. Magn Reson Med 66:1432-44|
|Paudyal, Ramesh; Ewing, James R; Nagaraja, Tavarekere N et al. (2011) The concordance of MRI and quantitative autoradiography estimates of the transvascular transfer rate constant of albumin in a rat brain tumor model. Magn Reson Med 66:1422-31|
|Bagher-Ebadian, Hassan; Paudyal, Ramesh; Nagaraja, Tavarekere N et al. (2011) MRI estimation of gadolinium and albumin effects on water proton. Neuroimage 54 Suppl 1:S176-9|
|Nagaraja, Tavarekere N; Karki, Kishor; Ewing, James R et al. (2010) The MRI-measured arterial input function resulting from a bolus injection of Gd-DTPA in a rat model of stroke slightly underestimates that of Gd-[14C]DTPA and marginally overestimates the blood-to-brain influx rate constant determined by Patlak plots. Magn Reson Med 63:1502-9|
Showing the most recent 10 out of 12 publications