Gliomas result in more years of life lost than any other cancer type. GBM is the most aggressive form of glioma, whereas oligodendroglioma (oligo) and astrocytoma (astro) tumors are characterized by a slower growth rate and longer survival. However, they affect a younger population and, because they are highly invasive, almost uniformly result in patient death. There is therefore an increasing focus on more aggressive treatments for oligo and astro patients. In particular, temozolomide (TMZ) and PI3K pathway inhibitors (PI3Kis) are currently in clinical trials. However, imaging of oligo and astro tumors and monitoring their response to therapy can be challenging, and new approaches are needed. The goal of this study is to identify and mechanistically validate magnetic resonance spectroscopy (MRS) - based metabolic imaging biomarkers of oligo and astro response to therapy. Our preliminary MRS data indicate that treatment with TMZ or PI3Kis leads to modulation of tricarboxylic acid (TCA) cycle flux and intracellular glutamate and glutamine levels but does not affect lactate production, consistent with gene expression data indicating a central role for the TCA cycle, but not for lactate synthesis, in oligos and astros. In addition, our preliminary data show that in TMZ-treated cells 6-phosphogluconate levels produced from hyperpolarized glucose are elevated, indicating an increase in flux towards the pentose phosphate pathway. We therefore hypothesize that metabolic imaging of the TCA cycle and pentose phosphate pathway can serve to inform on oligo and astro response to therapy. Based on this hypothesis we propose to investigate unique recently developed genetically characterized patient-derived oligo and astro models, and to develop new MRS biomarkers of response to treatment via the following Aims.
Aim 1. To identify 1H and HP 13C MRS biomarkers of oligodendroglioma and astrocytoma response to therapy in neurosphere models. We will investigate control and treated oligo and astro neurospheres, as well as GBM neurospheres, and use 1H and HP 13C MRS to identify metabolic alterations that inform on oligo and astro response to TMZ or PI3Kis.
Aim 2. To determine the translational value of 1H and HP 13C MRS biomarkers by monitoring therapeutic response in orthotopic tumors in vivo. We will investigate control and treated oligo and astro tumor-bearing mice and determine the value of 1H and HP 13C MRS biomarkers identified in Aim 1 to inform on drug-target engagement and predict response to therapy with TMZ or PI3Kis.
Aim 3. To validate the metabolic biomarkers by mechanistically linking metabolic findings with drug action. We will investigate neurospheres from Aim 1 and excised tumors from Aim 2 and use biochemical and cell biological assays to validate our imaging biomarkers by determining the underlying mechanism for their modulation by treatment.
The proposed research will identify and validate new magnetic resonance metabolic imaging approaches that will enhance current imaging methods and help predict oligodendroglioma and astrocytoma response to therapy in a personalized way. This approach will serve to improve noninvasive, precision-medicine imaging of response to current and emerging therapies, resulting in improved care for oligodendroglioma and astrocytoma patients.
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