Spatial Mapping of Phospholipid Biosynthesis in Brain Tumors

PROJECT SUMMARY Glioblastomas (GBMs) are malignant primary brain tumors in adults. Standard of care involves maximal safe surgical resection, radiation, and chemotherapy with temozolomide. Novel therapies are also under development for GBM patients. However, physicians are hampered in their efforts to effectively treat GBM

patients by their inability to reliably monitor tumor growth in vivo. Specifically, disease progression and treatment response in GBM patients are typically monitored by non-invasive magnetic resonance imaging (MRI) methods such as contrast-enhanced MRI. However, contrast enhancement reflects the integrity of the

blood brain barrier rather than any intrinsic biological activity of the tumor. As a result, it becomes difficult to reliably determine response to therapy. Tumors reprogram their metabolism to generate the biosynthetic precursors needed for proliferation. Phosphatidylcholine is the main structural component of all cellular membranes, and its biosynthesis is

upregulated in most cancers due to the high membrane turnover associated with uncontrolled proliferation. The dietary nutrient choline is converted to phosphocholine (PC), which is subsequently incorporated into phosphatidylcholine. Expression of the key enzyme in this pathway, choline kinase α (CKα), is elevated in

tumors relative to surrounding normal tissues, including in GBMs. Non-invasive methods of imaging CKα activity will provide the unique opportunity to visualize tumor intrinsic biological activity in vivo. Deuterium magnetic resonance spectroscopy recently emerged as an innovative clinically translatable method

of imaging the metabolism of stable, non-radioactive, deuterated molecules in vivo. Our goal is to determine whether mapping CKα activity using deuterated choline enables non-invasive assessment of GBM response to therapy in vivo. We will examine the ability of deuterated choline to spatially map CKα activity (Aim 1) and

provide a readout of GBM response to therapy (Aim 2) in vivo at the clinical field strength of 3T. For both aims, we will use complementary biochemical assays to confirm our DMRS data and correlate it with tumor biology. Our proposal is innovative and impactful because it will validate deuterated choline as a specific, safe, non-

radioactive tracer for imaging GBM growth in vivo. By doing so, our proposal will enable precision imaging that significantly improves outcomes and quality of life for GBM patients.