Exploiting Altered Porphyrin Synthesis for Metabolic Imaging of Glioblastoma

NIH的使命是支持“病因、诊断、预防、

In keeping with the mission of the NIH to support research “with respect to the cause, diagnosis, prevention, and treatment of cancer” (NCI) and “of new biomedical imaging and bioengineering techniques and devices to fundamentally improve the detection, treatment, and prevention of disease” (NIBIB), the overarching goal of this proposal is to leverage metabolic alterations in cancer cells for the noninvasive diagnosis and characterization of glioblastoma (GBM), the most deadly and common primary brain cancer in adults. GBM takes more than 13,000 lives in the USA each year and is defined by multiple, complex genetic subtypes and tumor invasion into adjacent brain tissue. Emerging dilemmas in the management of patients with GBM include characterizing the tumor-specific alterations that occur over time and in response to therapies. One strategy is to define and analyze these alterations using real-time information on the molecular level acquired with advanced imaging techniques. This strategy has the potential to differentiate genetic and loco-regional tumor variations as well as evaluate and monitor treatment responses. Specifically, the in vivo visualization of tumor- specific metabolic pathways is likely to add greatly to the diagnostic information used to effectively manage patients with GBM. One such pathway is the conversion of 5-aminolevulinic acid (5-ALA, a naturally occurring substrate) to protoporphyrin IX (PpIX, the fluorescent product) during heme biosynthesis. This pathway is highly and selectively upregulated in 90% of GBMs and increasing levels of PpIX have been identified within regions of increasing tumor grade. The recent development of hyperpolarized 13C magnetic resonance spectroscopy (MRS) enables for the first time the real-time non-invasive measurement of critical dynamic metabolic processes in vivo. Here, we propose to develop a hyperpolarized 13C MRS-based approach for noninvasive assessment of GBM by exploiting the altered porphyrin metabolism of cancer cells. Firstly, we will synthesize 5-ALA 13C-substituted in specific positions and optimize the substrate formulation to achieve maximum polarization, which directly translates into higher signal amplification when used as an imaging agent (Aim 1). Secondly, we will evaluate the feasibility of using hyperpolarized 13C-5-ALA as molecular imaging agent to measure the altered porphyrin metabolism in GBM, first in a series of in vitro cell experiments and then in a rat model of GBM (Aim 2). Given that hyperpolarized 13C MRS is being actively investigated in patients with numerous diseases, the successful completion of this high-risk/high-reward project has the potential to provide a noninvasive approach for the diagnosis, monitoring, and therapeutic evaluation of GBM patients.