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
Lupo, Janine M; Molinaro, Annette M; Essock-Burns, Emma et al. (2016) The effects of anti-angiogenic therapy on the formation of radiation-induced microbleeds in normal brain tissue of patients with glioma. Neuro Oncol 18:87-95
Mazor, Tali; Pankov, Aleksandr; Song, Jun S et al. (2016) Intratumoral Heterogeneity of the Epigenome. Cancer Cell 29:440-51
Park, Ilwoo; von Morze, Cornelius; Lupo, Janine M et al. (2016) Investigating tumor perfusion by hyperpolarized (13) C MRI with comparison to conventional gadolinium contrast-enhanced MRI and pathology in orthotopic human GBM xenografts. Magn Reson Med :
Johannessen, Tor-Christian Aase; Mukherjee, Joydeep; Viswanath, Pavithra et al. (2016) Rapid Conversion of Mutant IDH1 from Driver to Passenger in a Model of Human Gliomagenesis. Mol Cancer Res 14:976-983
Cao, Peng; Shin, Peter J; Park, Ilwoo et al. (2016) Accelerated high-bandwidth MR spectroscopic imaging using compressed sensing. Magn Reson Med 76:369-79
Larson, Peder E Z; Han, Misung; Krug, Roland et al. (2016) Ultrashort echo time and zero echo time MRI at 7T. MAGMA 29:359-70
Radoul, Marina; Chaumeil, Myriam M; Eriksson, Pia et al. (2016) MR Studies of Glioblastoma Models Treated with Dual PI3K/mTOR Inhibitor and Temozolomide:Metabolic Changes Are Associated with Enhanced Survival. Mol Cancer Ther 15:1113-22
Bell, Robert J A; Rube, H Tomas; Xavier-Magalhães, Ana et al. (2016) Understanding TERT Promoter Mutations: A Common Path to Immortality. Mol Cancer Res 14:315-23
Nelson, Sarah J; Li, Yan; Lupo, Janine M et al. (2016) Serial analysis of 3D H-1 MRSI for patients with newly diagnosed GBM treated with combination therapy that includes bevacizumab. J Neurooncol 130:171-179
Cao, Peng; Zhang, Xiaoliang; Park, Ilwoo et al. (2015) (1) H-(13) C independently tuned radiofrequency surface coil applied for in vivo hyperpolarized MRI. Magn Reson Med :

Showing the most recent 10 out of 51 publications