Patients with brain tumors are in desperate need of new therapies. Recent clinical studies combining anti- angiogenic agents with conventional therapies have shown significant improvements in patient response leading to the first FDA-approved anti-angiogenic agents. Yet, to fully realize the promise of combined therapies, we need non-invasive methods that can answer critical questions about how these agents work and how to combine them optimally. Thus, the overall goal of this research, which is to develop and validate DSC (dynamic susceptibility contrast) MRI methods to monitor tumor angiogenesis and vascular normalization, is quite relevant and timely. We have characterized susceptibility-based biophysical relationships in tumors and developed a GE-SE (gradient-echo/spin-echo) method, with contrast-leakage correction, to provide measures of total (GE) and microvascular (SE) cerebral blood volume (CBV), mean vessel diameter (mVD) cerebral blood flow (CBF), and mean transit time (MTT). We have shown these to correlate with tumor grade, guide intraoperative diagnosis and distinguish radiation effects from tumor recurrence. We demonstrated a dose-dependent response to anti-angiogenic therapy in rat brain tumors, and an effect suggestive of vascular normalization, which may explain the success of combined therapies.
The specific aims are logical and exciting extensions of this work. We will continue to characterize and validate the accuracy of susceptibility contrast agent methods i. by comparing MRI and microscopy measures of CBV and mVD in rat brain tumor models and ii. by using a novel tumor-specific DSC simulation model developed by us (Aim 1). The ability of DSC methods to identify vascular normalization, and thus optimize treatment timing, will be determined with combined anti-angiogenic and radiation therapy studies in animals (Aim 2). Translation of the leakage-corrected GE/SE results to a wider scientific and clinical audience requires the comparison of our approach to other acquisition and analysis methods (Aim 3). Finally, the utility of multiparameter DSC methods to predict survival and track response to anti-angiogenic therapies will be tested in patients (Aim 4). Thus, completion of this study should improve the application and interpretation of DSC methods for the evaluation of tumor angiogenesis and combined therapeutic strategies so that it will ultimately be accepted into routine clinical practice for the benefit of brain tumor patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA082500-12
Application #
8015291
Study Section
Medical Imaging Study Section (MEDI)
Program Officer
Zhang, Huiming
Project Start
2000-03-01
Project End
2012-04-30
Budget Start
2011-02-01
Budget End
2012-04-30
Support Year
12
Fiscal Year
2011
Total Cost
$275,179
Indirect Cost
Name
Medical College of Wisconsin
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Nguyen, H S; Milbach, N; Hurrell, S L et al. (2016) Progressing Bevacizumab-Induced Diffusion Restriction Is Associated with Coagulative Necrosis Surrounded by Viable Tumor and Decreased Overall Survival in Patients with Recurrent Glioblastoma. AJNR Am J Neuroradiol 37:2201-2208
Jafari-Khouzani, Kourosh; Emblem, Kyrre E; Kalpathy-Cramer, Jayashree et al. (2015) Repeatability of Cerebral Perfusion Using Dynamic Susceptibility Contrast MRI in Glioblastoma Patients. Transl Oncol 8:137-46
Prah, M A; Stufflebeam, S M; Paulson, E S et al. (2015) Repeatability of Standardized and Normalized Relative CBV in Patients with Newly Diagnosed Glioblastoma. AJNR Am J Neuroradiol 36:1654-61
Schmainda, Kathleen M; Zhang, Zheng; Prah, Melissa et al. (2015) Dynamic susceptibility contrast MRI measures of relative cerebral blood volume as a prognostic marker for overall survival in recurrent glioblastoma: results from the ACRIN 6677/RTOG 0625 multicenter trial. Neuro Oncol 17:1148-56
Cohen, Alexander D; Schieke, Moira C; Hohenwalter, Mark D et al. (2015) The effect of low b-values on the intravoxel incoherent motion derived pseudodiffusion parameter in liver. Magn Reson Med 73:306-11
Boxerman, Jerrold L; Schmainda, Kathleen M; Zhang, Zheng et al. (2015) Dynamic susceptibility contrast MRI measures of relative cerebral blood volume continue to show promise as an early response marker in the setting of bevacizumab treatment. Neuro Oncol 17:1538-9
LaViolette, Peter S; Mickevicius, Nikolai J; Cochran, Elizabeth J et al. (2014) Precise ex vivo histological validation of heightened cellularity and diffusion-restricted necrosis in regions of dark apparent diffusion coefficient in 7 cases of high-grade glioma. Neuro Oncol 16:1599-606
LaViolette, Peter S; Daun, Mitchell K; Paulson, Eric S et al. (2014) Effect of contrast leakage on the detection of abnormal brain tumor vasculature in high-grade glioma. J Neurooncol 116:543-9
Schmainda, Kathleen M; Prah, Melissa; Connelly, Jennifer et al. (2014) Dynamic-susceptibility contrast agent MRI measures of relative cerebral blood volume predict response to bevacizumab in recurrent high-grade glioma. Neuro Oncol 16:880-8
LaViolette, Peter S; Cohen, Alex D; Prah, Melissa A et al. (2013) Vascular change measured with independent component analysis of dynamic susceptibility contrast MRI predicts bevacizumab response in high-grade glioma. Neuro Oncol 15:442-50

Showing the most recent 10 out of 41 publications