The goal of the proposed research is to develop and mechanistically validate MR-detectable metabolic biomarkers in order to evaluate the molecular response of glioblastoma multiforme (GBM) to novel therapies that target oncogenic signaling pathways, which are activated within such lesions. The median survival for GBM patients is less than eighteen months, and new therapies are essential to improve outcome. A promising therapeutic approach is to target the PI3K/AKT/mTOR pathway, which is activated in 88% of GBM tumors. However, a critical issue with such novel treatments is that drug activity often results in tumor stasis, and current imaging methods do not inform upon drug action. The proposed research will use a previously unexplored approach to address this unmet need. PI3K/AKT/mTOR signaling modulates the conversion of pyruvate into lactate as well as the synthesis of phosphocholine (PC). We hypothesize that levels of PC, detectable by monitoring total choline-containing metabolites (tCho) by 1H MRS, and levels of hyperpolarized lactate, detectable by monitoring hyperpolarized pyruvate metabolism using 13C MRS, can serve as linked downstream biomarkers of PI3K/AKT/mTOR signaling and provide a metabolic read-out of drug-target modulation by agents that inhibit this signaling. Our strategy in the proposed research is first to use non-invasive MR techniques in tumor model systems to monitor changes in tCho and hyperpolarized lactate and to validate their role in detecting molecular response to emerging PI3K/AKT/mTOR inhibitors. After confirming the biological significance of these parameters in a pre-clinical setting, MR techniques will be applied to patients with GBM who are participating in state of the art clinical trials.
Aim 1. To apply 31P, 1H and hyperpolarized 13C MRS as well as complementary biological assays to control and PI3K/AKT/mTOR inhibitor-treated GBM cells with different genetic backgrounds in order to validate PC, tCho and hyperpolarized lactate as biomarkers of molecular response to therapy.
Aim 2. To apply 1H MRSI, hyperpolarized 13C MRSI and complementary biological assays to control and PI3K/AKT/mTOR inhibitor-treated rat orthotopic GBM tumors with different genetic backgrounds in order to validate the role of tCho and hyperpolarized lactate as biomarkers of molecular response to therapy in vivo.
Aim 3. To apply 1H MRSI and hyperpolarized 13C MRSI to patients with newly diagnosed GBM who are being treated with standard of care radiotherapy (RT) and temozolomide in combination with PI3K/AKT/mTOR inhibitors in order to validate the role of in vivo tCho and lactate as biomarkers of response to therapy. The proposed research will result in an imaging method that can inform on drug delivery and molecular response. It will enable longitudinal monitoring of drug action at the tumor site and will provide a tool to optimize therapeutic regimens, resulting in more personalized care and improved outcome for GBM patients.

Public Health Relevance

The proposed research will address the currently unmet need for a non-invasive in vivo imaging method to monitor the effect of emerging new therapies that target the PI3K pathway, a signaling pathway that is central in cancer. This type of imaging will inform on drug delivery and response, and will enable longitudinal monitoring of drug action at the tumor site. It will provide a tool to help optimize therapeutic regimens that are specifically tailored to the individual tumor and will result in more personalized patient care and enhanced quality of life and outcome.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-DTCS-A (81))
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Zhang, Huiming
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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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
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Viswanath, Pavithra; Chaumeil, Myriam M; Ronen, Sabrina M (2016) Molecular Imaging of Metabolic Reprograming in Mutant IDH Cells. Front Oncol 6:60
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Viswanath, Pavithra; Najac, Chloe; Izquierdo-Garcia, Jose L et al. (2016) Mutant IDH1 expression is associated with down-regulation of monocarboxylate transporters. Oncotarget 7:34942-55
Viswanath, Pavithra; Ronen, Sabrina M (2016) Metabolic reprogramming of pyruvate dehydrogenase is essential for the proliferation of glioma cells expressing mutant IDH1. Mol Cell Oncol 3:e1077922
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
Izquierdo-Garcia, Jose L; Viswanath, Pavithra; Eriksson, Pia et al. (2015) IDH1 Mutation Induces Reprogramming of Pyruvate Metabolism. Cancer Res 75:2999-3009
Izquierdo-Garcia, Jose L; Viswanath, Pavithra; Eriksson, Pia et al. (2015) Metabolic reprogramming in mutant IDH1 glioma cells. PLoS One 10:e0118781

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