Standard clinical assessment of brain tumor response to treatment consists of examining contrast enhancement and T2-weighted signal abnormalities on standard magnetic resonance imaging (MRI) scans. While these techniques provide important information regarding tumor pathophysiology, they do not enable direct visualization of tumor growth and invasion. Numerous studies over the past 20 years have shown that tumor cell invasion extends well beyond the margins of abnormalities detected on traditional MRI scans, and this invasion is the primary reason for poor prognosis and 100% fatality rate in glioblastoma multiforme (GBM), the most common and malignant type of brain tumor. Therefore, the overall goal of this project is to establish a valuable clinical imaging biomarker fr visualization and quantification of brain tumor growth and invasion using diffusion MRI techniques. We have demonstrated in our preliminary data that diffusion MRI is sensitive to tumor cell density, and voxel-wise changes in diffusion MRI over time can be used to predict the response to both chemotherapy and anti-angiogenic therapies. In a recent manuscript, we have developed a novel spatiotemporal model of ADC change aimed at quantifying voxel-wise microscopic proliferation and cell invasion rates termed Cell Invasion, Motility, and Proliferation Level Estimate (CIMPLE) maps. Our preliminary data suggests CIMPLE maps correlate with MR spectroscopy measurements of malignant potential, correlate with tumor grade, may predict regions of future contrast enhancement, predict survival in patients with recurrent glioblastoma treated with bevacizumab, and spatially correlates well with abnormal positron emission tomography measurements of amino acid uptake. Despite promising preliminary results from our laboratory, more testing and improvements are necessary as outlined in the specific experiments in the current proposal.
Specific Aim #1 focuses on improving the diffusion-weighted image acquisition for advanced CIMPLE map applications by exploring the use of high angular resolution diffusion imaging (HARDI). Success of this specific aim will allow CIMPLE maps to be calculated with high accuracy through higher signal-to-noise diffusion images as well as create a tensor-based solution to CIMPLE maps that may provide directionally-specific maps of tumor invasion.
Specific Aim #2 will focus on testing whether CIMPLE maps calculated during radiotherapy are early predictive biomarkers of tumor response to standard therapy. Specifically, we aim to determine whether CIMPLE maps accurately predict spatial regions of future tumor progression as well as predict six- and twelve-month progression-free and overall survival. Lastly, Specific Aim #3 will focus on validating CIMPLE maps through the use of histological information at tumor recurrence and 18F-fluoro-thymidine positron emission tomography measurements of tumor proliferation. Successful completion of this aim will provide additional evidence validating non-invasive CIMPLE map measurements of proliferation and invasion rate.

Public Health Relevance

There is a general consensus in the neuro-oncology community that current methods of monitoring malignant glioma growth and response to treatment are inadequate, particularly when trying to detect brain tumor invasion. This project aims to further establish, validate, and clinically translate CIMPLE maps as a non-invasive imaging surrogate for quantification of tumor cell invasion and proliferation in gliomas. Successful completion of this project will help establish CIMPLE maps as a personalized clinical monitoring tool that will help tailor drug selection and detect drug failure in individual patients much sooner than conventional techniques.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA167354-01
Application #
8283486
Study Section
Cancer Biomarkers Study Section (CBSS)
Program Officer
Zhang, Yantian
Project Start
2012-09-17
Project End
2014-08-31
Budget Start
2012-09-17
Budget End
2013-08-31
Support Year
1
Fiscal Year
2012
Total Cost
$200,971
Indirect Cost
$70,471
Name
University of California Los Angeles
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Zaw, Taryar M; Pope, Whitney B; Cloughesy, Timothy F et al. (2014) Short-interval estimation of proliferation rate using serial diffusion MRI predicts progression-free survival in newly diagnosed glioblastoma treated with radiochemotherapy. J Neurooncol 116:601-8
Woodworth, Davis C; Pope, Whitney B; Liau, Linda M et al. (2014) Nonlinear distortion correction of diffusion MR images improves quantitative DTI measurements in glioblastoma. J Neurooncol 116:551-8
Tran, Anh N; Lai, Albert; Li, Sichen et al. (2014) Increased sensitivity to radiochemotherapy in IDH1 mutant glioblastoma as demonstrated by serial quantitative MR volumetry. Neuro Oncol 16:414-20
Harris, Robert J; Bookheimer, Susan Y; Cloughesy, Timothy F et al. (2014) Altered functional connectivity of the default mode network in diffuse gliomas measured with pseudo-resting state fMRI. J Neurooncol 116:373-9
Ellingson, Benjamin M; Cloughesy, Timothy F; Lai, Albert et al. (2013) Quantitative probabilistic functional diffusion mapping in newly diagnosed glioblastoma treated with radiochemotherapy. Neuro Oncol 15:382-90
Harris, Robert J; Cloughesy, Timothy F; Pope, Whitney B et al. (2013) Pre- and post-contrast three-dimensional double inversion-recovery MRI in human glioblastoma. J Neurooncol 112:257-66
Naeini, Kourosh M; Pope, Whitney B; Cloughesy, Timothy F et al. (2013) Identifying the mesenchymal molecular subtype of glioblastoma using quantitative volumetric analysis of anatomic magnetic resonance images. Neuro Oncol 15:626-34
Ellingson, Benjamin M; Mayer, Emeran; Harris, Robert J et al. (2013) Diffusion tensor imaging detects microstructural reorganization in the brain associated with chronic irritable bowel syndrome. Pain 154:1528-41