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. !
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. !
|Viswanath, Pavithra; Radoul, Marina; Izquierdo-Garcia, Jose Luis et al. (2018) 2-Hydroxyglutarate-Mediated Autophagy of the Endoplasmic Reticulum Leads to an Unusual Downregulation of Phospholipid Biosynthesis in Mutant IDH1 Gliomas. Cancer Res 78:2290-2304|
|Viswanath, Pavithra; Radoul, Marina; Izquierdo-Garcia, Jose Luis et al. (2018) Mutant IDH1 gliomas downregulate phosphocholine and phosphoethanolamine synthesis in a 2-hydroxyglutarate-dependent manner. Cancer Metab 6:3|
|Taglang, Céline; Korenchan, David E; von Morze, Cornelius et al. (2018) Late-stage deuteration of 13C-enriched substrates for T1 prolongation in hyperpolarized 13C MRI. Chem Commun (Camb) 54:5233-5236|
|Guglielmetti, Caroline; Najac, Chloé; 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|
|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|
|Jalbert, Llewellyn E; Elkhaled, Adam; Phillips, Joanna J et al. (2017) Metabolic Profiling of IDH Mutation and Malignant Progression in Infiltrating Glioma. Sci Rep 7:44792|
|Guglielmetti, Caroline; Chou, Austin; Krukowski, Karen et al. (2017) In vivo metabolic imaging of Traumatic Brain Injury. Sci Rep 7:17525|
|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|
|Chaumeil, Myriam M; Radoul, Marina; Najac, Chloé 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|
|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|
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