The overall goal of this competitive RO1 renewal is to develop and validate MRI biomarkers to monitor treatment response in patients with brain tumors. This development addresses a timely and urgent clinical need for new ways to monitor the newly-incorporated chemotherapeutic and anti-angiogenic therapies, for which standard measures of enhancing tumor volumes are no longer sufficient. Given our recent developments in both PWI and DWI in brain tumors, we are well-positioned to address this need. The PI has been a leader in the field of PWI technology for brain tumors for over 12 years. During the last funding cycle a novel dual-echo gradient-echo spiral-based (DEGES) approach to perfusion imaging was invented. The DEGES approach enables the simultaneous acquisition of dynamic susceptibility contrast (DSC) and dynamic contrast enhanced (DCE)-MRI perfusion data using only a single dose of gadolinium (Gd) contrast agent, followed by complete post-processing correction of both T1 and T2/T2* contrast agent leakage effects. With the planned studies to optimize and validate this approach (Aim 1) we hypothesize that DEGES will prove to be the most accurate and comprehensive solution to PWI in brain tumors, and may therefore become the standard approach. In addition, we have put forth great effort, evidenced by several recent publications, to develop and validate DWI methods to monitor brain tumor growth, especially in areas of non-enhancing invading tumor. By computing changes in the apparent diffusion coefficient (ADC) across time, we have created functional diffusion maps (fDM) and found that changes in ADC, suggestive of increased cellularity, were more predictive of response to the anti-angiogenic drug, bevacizumab, than standard contrast-agent enhanced MRI. These developments in both PWI and DWI have positioned us well to develop biomarkers to distinguish true changes in tumor growth from the increasingly common pseudo responses, the focus of the Aim 2 studies. Finally, during the last four years we have demonstrated the potential of DSC-MRI derived rCBV (relative cerebral blood volume) to predict tumor response earlier and more accurately than standard contrast agent enhanced tumor volumes in patients and experimental rat models, and provide information relevant to the characterization and optimization of combined therapies. These studies will continue but with an added emphasis on invasion, and anti-invasion therapies in combination with anti-angiogenic drugs. It is becoming increasingly clear that there exists a complex relationship between angiogenesis and invasion that must be better understood and monitored if significant progress in brain tumor treatments can be made. Overall, this proposal has an exceptionally high likelihood of having a profound impact on the clinical treatment and monitoring of brain tumor patients with the introduction of a validated robust PWI technology to monitor tumor angiogenesis in combination with promising DWI methods to monitor invasion. This in turn could lead to the development of new drugs and therapeutic strategies, in general and on an individualized basis, which will ultimately lead to improved patient outcomes.

Public Health Relevance

This RO1 competitive renewal proposes the development and validation of a combined perfusion and diffusion MRI (magnetic resonance imaging) approach to monitor the growth and treatment of brain tumors. Given that standard MRI methods to monitor treatment response have been found lacking this addresses an urgent clinical need. The perfusion technology is based on developments made over the past twelve years in the PI's laboratory and therefore may represent the most comprehensive and accurate solution to monitoring tumor vessel growth. This combined with recent advances in diffusion imaging, which provide complementary information about tumor cell invasion, has the potential to change the way by which brain tumor treatments are monitored and aid in the discovery of new treatments and combinations.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA082500-14
Application #
8462918
Study Section
Special Emphasis Panel (ZRG1-DTCS-U (81))
Program Officer
Zhang, Huiming
Project Start
2000-03-01
Project End
2017-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
14
Fiscal Year
2013
Total Cost
$273,041
Indirect Cost
$61,072
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
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Ellingson, Benjamin M; Malkin, Mark G; Rand, Scott D et al. (2011) Volumetric analysis of functional diffusion maps is a predictive imaging biomarker for cytotoxic and anti-angiogenic treatments in malignant gliomas. J Neurooncol 102:95-103
Darpolor, Moses M; Molthen, Robert C; Schmainda, Kathleen M (2011) Multimodality imaging of abnormal vascular perfusion and morphology in preclinical 9L gliosarcoma model. PLoS One 6:e16621
Ellingson, Benjamin M; Cloughesy, Timothy F; Lai, Albert et al. (2011) Graded functional diffusion map-defined characteristics of apparent diffusion coefficients predict overall survival in recurrent glioblastoma treated with bevacizumab. Neuro Oncol 13:1151-61

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