The goal of this application is to test the hypothesis that the neomorphic activity of mutant isocitrate dehydrogenase (IDH) results not only in production of the oncometabolite 2-hydroxygluatarte (2-HG), but also in a wider metabolic reprogramming which is essential for tumor progression and therefore can be targeted in the treatment of IDH-mutant gliomas. A secondary goal is to identify novel imaging biomarkers for monitoring the normalization of this metabolic reprogramming with treatment. IDH is the enzyme that catalyzes the oxidative decarboxylation of isocitrate to ?-ketoglutarate (?-KG). Mutant IDH catalyzes the conversion of ?-KG into 2-HG. Mutations in IDH and elevated 2-HG occur in over 70% of gliomas and secondary glioblastomas (GBM) and the IDH mutation is an early event associated with initiation of low grade brain tumors. 1H magnetic resonance spectroscopy (MRS) investigations of patient biopsies performed at UCSF confirmed that 2-HG levels correlate with mutant IDH expression. In addition, several other alterations in steady state metabolite levels were observed. Preliminary studies of cells engineered to express mutant IDH recapitulated the 1H MRS-detectable metabolic changes observed in patient samples and13C MRS confirmed that ?-KG is preferentially converted to 2-HG in mutant IDH cells. Furthermore, fluxes via metabolic pathways through which ?-KG can be replenished were found to be elevated and inhibition of one such pathway resulted in inhibition of cellular proliferation in mutant IDH cells. These findings form the basis of our hypothesis that mutant IDH leads to a metabolic reprogramming that is essential for mutant IDH tumor growth. We propose to test this hypothesis in a GBM-based model as well as in novel immortalized astrocyte and glial progenitor models via the following aims.
Aim 1. To measure flux via specific metabolic pathways in wild-type and mutant IDH cells in order to determine which metabolic pathways are altered by mutant IDH. We will study wild-type and mutant IDH cells and use 13C MRS with 13C-labeled metabolic precursors (hyperpolarized and thermally polarized) as well as 1H MRS and complementary biological methods to probe the metabolic pathways that control the steady state levels of metabolites modulated by mutant IDH.
Aim 2. To determine whether the metabolic changes associated with mutant IDH are essential for cell transformation and proliferation. We will modulate the specific metabolic pathways that are altered in mutant IDH cells and determine the consequences of this inhibition on cell proliferation and tumorigenicity.
Aim 3. To investigate mutant IDH orthotopic brain tumors in vivo in order to determine the effect of metabolic modulation and to identify MR-based biomarkers of response to metabolic modulation. We will use MRI, 1H and 13C MRS/I as well as complementary biological assays to investigate the effect of inhibiting metabolism on mutant IDH tumor growth and MRS-detectable biomarkers. !

Public Health Relevance

The proposed research aims to characterize the metabolism of brain tumors that harbor the recently discovered IDH mutation and in so doing to identify novel therapeutic approaches for the treatment of mutant IDH gliomas as well as other cancers that harbor the IDH mutation. The proposed research will also identify imaging biomarkers that can be used to monitor the effect of such therapies. This innovative study could thus provide a tool to help optimize therapeutic regimens that are tailored to the mutant IDH genotype resulting in more personalized care for patients, enhancing their quality of life and potentially outcome. !

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA172845-01
Application #
8421781
Study Section
Clinical Molecular Imaging and Probe Development (CMIP)
Program Officer
Spalholz, Barbara A
Project Start
2013-02-05
Project End
2018-01-31
Budget Start
2013-02-05
Budget End
2014-01-31
Support Year
1
Fiscal Year
2013
Total Cost
$633,200
Indirect Cost
$229,352
Name
University of California San Francisco
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Mazor, Tali; Chesnelong, Charles; Pankov, Aleksandr et al. (2017) Clonal expansion and epigenetic reprogramming following deletion or amplification of mutant IDH1. Proc Natl Acad Sci U S A 114:10743-10748
Roy, Srirupa; Leidal, Andrew M; Ye, Jordan et al. (2017) Autophagy-Dependent Shuttling of TBC1D5 Controls Plasma Membrane Translocation of GLUT1 and Glucose Uptake. Mol Cell 67:84-95.e5
Guglielmetti, Caroline; Najac, ChloƩ; Didonna, Alessandro et al. (2017) Hyperpolarized 13C MR metabolic imaging can detect neuroinflammation in vivo in a multiple sclerosis murine model. Proc Natl Acad Sci U S A 114:E6982-E6991
Guglielmetti, Caroline; Chou, Austin; Krukowski, Karen et al. (2017) In vivo metabolic imaging of Traumatic Brain Injury. Sci Rep 7:17525
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
Chaumeil, Myriam M; Radoul, Marina; Najac, ChloƩ et al. (2016) Hyperpolarized (13)C MR imaging detects no lactate production in mutant IDH1 gliomas: Implications for diagnosis and response monitoring. Neuroimage Clin 12:180-9
Cao, Peng; Zhang, Xiaoliang; Park, Ilwoo et al. (2016) 1 H-13 C independently tuned radiofrequency surface coil applied for in vivo hyperpolarized MRI. Magn Reson Med 76:1612-1620
Viswanath, Pavithra; Chaumeil, Myriam M; Ronen, Sabrina M (2016) Molecular Imaging of Metabolic Reprograming in Mutant IDH Cells. Front Oncol 6:60
Reed, Galen D; von Morze, Cornelius; Verkman, Alan S et al. (2016) Imaging Renal Urea Handling in Rats at Millimeter Resolution using Hyperpolarized Magnetic Resonance Relaxometry. Tomography 2:125-135
Ohba, Shigeo; Mukherjee, Joydeep; Johannessen, Tor-Christian et al. (2016) Mutant IDH1 Expression Drives TERT Promoter Reactivation as Part of the Cellular Transformation Process. Cancer Res 76:6680-6689

Showing the most recent 10 out of 22 publications