The goal of this competitive renewal is to identify and validate novel translatable metabolic imaging biomarkers of response to advanced clinically-relevant therapies that target isocitrate dehydrogenase 1 (IDH1) in the treatment of mutant IDH1 glioma. The IDH1 mutation is a `driver mutation' that is present in 70-90% of low- grade glioma and secondary upgraded glioblastoma. In an effort to improve the treatment of mutant IDH1 tumors, novel therapeutic approaches are been developed, and data shows that siRNA targeting both wild-type (wt) and mutant IDH1, as well as new dual (wt/mutant) IDH inhibitors now in clinical trials, lead to a clear response. However, no noninvasive imaging methods are available to assess drug-target engagement or predict response. During the first funding period of this grant we identified several mutant IDH1-driven 1H magnetic resonance spectroscopy (MRS)-detectable metabolic alterations, and developed novel translational hyperpolarized 13C MRS-based imaging approaches that inform on the presence of the mutation. Our preliminary data indicate that response to treatment with emerging dual inhibitors is associated with a reversal of all the 1H MRS-detectable metabolic alterations observed in mutant cells but not with all of the associated hyperpolarized 13C MRS-detectable metabolic fluxes, likely reflecting inhibition of wt IDH1. In addition, levels of glutathione (GSH) and the ratio of GSH to its oxidized form GSSG drop, pointing to additional imageable metabolic reactions associated with response. We therefore hypothesize that using some of our previously identified MRS biomarkers of mutant IDH1, as well as imaging biomarkers of redox status, it will be possible to monitor the therapeutic effects of dual IDH inhibitors that are entering the clinic.
Aim 1. To identify 1H and hyperpolarized 13C MRS-detectable metabolic biomarkers associated with response to novel IDH-targeting therapies in mutant IDH1 cells. We will investigate genetically-engineered and patient-derived cell models, and use 1H and hyperpolarized 13C MRS to identify the imageable metabolic alterations that are uniquely associated with response to therapy as determined by inhibition in cell proliferation and/or clonogenic potential.
Aim 2. To mechanistically validate 1H and hyperpolarized 13C MRS imaging biomarkers of response. We will use a range of biochemical, cell, and molecular biological assays as well as specific inhibitors to determine the mechanistic link between drug action and the metabolic imaging biomarkers identified in Aim 1.
Aim 3. To confirm in vivo the 1H and hyperpolarized 13C MRS metabolic imaging biomarkers as indicators of tumor response to novel IDH-targeting therapies in mutant IDH1 tumors. We will treat tumor-bearing mice, and use MRI with 1H and hyperpolarized 13C MRSI, to longitudinally monitor the effect of therapy on tumor growth and metabolism, and assess the value of our metabolic imaging biomarkers for prediction of response as assessed by tumor size and/or animal survival.

Public Health Relevance

The proposed research builds on our previous findings and aims to identify and validate noninvasive magnetic resonance spectroscopy-based metabolic imaging biomarkers of response to emerging therapies that target mutant IDH1 gliomas and that are currently in clinical trials. As such, our study would improve patient care resulting in personalized precision care that will enhance the quality of life and potential outcome of mutant IDH1 glioma patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA172845-08
Application #
9868811
Study Section
Medical Imaging Study Section (MEDI)
Program Officer
Zhang, Huiming
Project Start
2013-02-05
Project End
2023-02-28
Budget Start
2020-03-01
Budget End
2021-02-28
Support Year
8
Fiscal Year
2020
Total Cost
Indirect Cost
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
94118
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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