Approximately 17,000 new cases of malignant brain cancer are diagnosed per year in the United States. Even with surgical resection, radiation, and chemotherapy, patients with glioblastoma (GBM), the most refractory form of the disease, typically succumb to the disease within 2 years of diagnosis. A major limitation in the development of effective therapies for recurrent GBM is the lack of a reliable method to predict early response to therapy. Monitoring response using conventional magnetic resonance (MR) imaging is often unreliable and are often unable to distinguish treatment effects from tumor response. In animal models of GBM, we recently found that response to temozolomide (TMZ) and PISK pathway inhibitors is associated with a tumor-specific decrease in the conversion of hyperpolarized carbon 13 (130) pyruvate to 13C lactate detectable by non invasive 130 MR spectroscopic imaging (MRSI) as a drop in the ratio of hyperpolarized lactate to pyruvate (Lac/Pyr). We therefore hypothesize that measurement of Lac/Pyr could serve as an early indicator of drug action in patients following treatment with TMZ, PI3K inhibitors, and potentially a range of other agents. This hypothesis will be tested by 1) defining in vitro sensitivity and verifying target inhibition in recurrent human GBM cells exposed to TMZ and other novel targeted agents including XL765 and SAHA 2) defining the effect of the drugs on the conversion of 130 pyruvate to 130 lactate in the drug sensitive/resistant paired GBM cells, and relating these changes to target inhibition and drug sensitivity, 3) determining if the drug-induced changes in 13C pyruvate to 130 lactate conversion that parallel target inhibition and drug sensitivity in vitro also do so in xenografts in vivo, and 4) determining if treatment-induced alterations in pyruvate metabolism detected by hyperpolarized 130 MRSI can be used alone, or in combination with other imaging markers, as a biomarker of target inhibition and early response in clinical trials of recurrent GBM patients. Close interactions with Project 1 and all the Shared Resource Cores will be critical to the successful conduct of the proposed studies.

Public Health Relevance

The proposed study will address the currently unmet need for a noninvasive imaging method to assess drug action in vivo, will develop a platform for testing the effect of novel agents on tumor metabolism, and will provide a tool to optimize therapeutic regimens specifically tailored to the tumor. It will save patients with GBM from the side effects of ineffective therapies and result in more personalized care.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA118816-07
Application #
8738072
Study Section
Special Emphasis Panel (ZCA1-RPRB-2)
Project Start
Project End
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
7
Fiscal Year
2014
Total Cost
$544,039
Indirect Cost
$199,213
Name
University of California San Francisco
Department
Type
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Mancini, Andrew; Xavier-Magalhães, Ana; Woods, Wendy S et al. (2018) Disruption of the ?1L Isoform of GABP Reverses Glioblastoma Replicative Immortality in a TERT Promoter Mutation-Dependent Manner. Cancer Cell 34:513-528.e8
Vareth, Maryam; Lupo, Janine; Larson, Peder et al. (2018) A comparison of coil combination strategies in 3D multi-channel MRSI reconstruction for patients with brain tumors. NMR Biomed 31:e3929
Li, Yan; Lafontaine, Marisa; Chang, Susan et al. (2018) Comparison between Short and Long Echo Time Magnetic Resonance Spectroscopic Imaging at 3T and 7T for Evaluating Brain Metabolites in Patients with Glioma. ACS Chem Neurosci 9:130-137
Gordon, Jeremy W; Chen, Hsin-Yu; Autry, Adam et al. (2018) Translation of Carbon-13 EPI for hyperpolarized MR molecular imaging of prostate and brain cancer patients. Magn Reson Med :
Choi, Serah; Yu, Yao; Grimmer, Matthew R et al. (2018) Temozolomide-associated hypermutation in gliomas. Neuro Oncol 20:1300-1309
Park, Ilwoo; Larson, Peder E Z; Gordon, Jeremy W et al. (2018) Development of methods and feasibility of using hyperpolarized carbon-13 imaging data for evaluating brain metabolism in patient studies. Magn Reson Med 80:864-873
Hayes, Josie; Yu, Yao; Jalbert, Llewellyn E et al. (2018) Genomic analysis of the origins and evolution of multicentric diffuse lower-grade gliomas. Neuro Oncol 20:632-641
Anwar, Mekhail; Molinaro, Annette M; Morin, Olivier et al. (2017) Identifying Voxels at Risk for Progression in Glioblastoma Based on Dosimetry, Physiologic and Metabolic MRI. Radiat Res 188:303-313
Venkatesan, Subramanian; Swanton, Charles; Taylor, Barry S et al. (2017) Treatment-Induced Mutagenesis and Selective Pressures Sculpt Cancer Evolution. Cold Spring Harb Perspect Med 7:
Zou, Xiaowei; Hart, Blaine L; Mabray, Marc et al. (2017) Automated algorithm for counting microbleeds in patients with familial cerebral cavernous malformations. Neuroradiology 59:685-690

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