Exploiting Altered Porphyrin Synthesis for Metabolic Imaging of Glioblastoma

根据美国国立卫生研究院的使命，支持“关于病因、诊断、预防、 和治疗癌症(NCI)和新的生物医学成像和生物工程技术和设备 从根本上改善疾病的检测、治疗和预防“(NIBIB)，这是 这项建议是利用癌细胞的代谢变化进行非侵入性诊断和 胶质母细胞瘤(GBM)是成人最致命和最常见的原发脑癌。GBM 在美国，每年有超过13,000人死于这种疾病，它由多种复杂的基因亚型和 肿瘤侵入邻近脑组织。GBM患者管理中新出现的困境包括 表征随着时间的推移和治疗反应而发生的肿瘤特异性改变。一种策略是 使用在分子水平上获得的实时信息来定义和分析这些变化 先进的成像技术。这一策略有可能区分遗传性肿瘤和局部肿瘤。 这些变化以及评估和监测治疗反应。具体地说，肿瘤的体内可视化- 特定的代谢途径可能极大地增加用于有效管理的诊断信息 肾小球基底膜病患者。一个这样的途径是5-氨基乙酰丙酸(5-ALA)的转化，5-ALA是一种自然发生的 在血红素生物合成过程中(底物)到原卟啉IX(PpIX，荧光产物)。这条路是 在90%的GBM中高度和选择性地上调，并在 肿瘤分级增高的区域。超极化~(13)C磁共振的研究进展 光谱学(MRS)首次实现了对关键动态的实时非侵入性测量 体内代谢过程。在这里，我们建议开发一种基于超极化13C MRS的方法 利用癌细胞的卟啉代谢改变对基底膜的非侵入性评估。首先，我们将 合成特定位置的5-丙氨酸13C取代物并优化底物配方以实现 最大偏振，用作显像剂时直接转化为更高的信号放大 (目标1)。其次，我们将评估超极化13C-5-ALA作为分子成像的可行性 用于测量GBM中改变的卟啉代谢的试剂，这是一系列体外细胞实验和 然后在GBM大鼠模型中(目标2)。 鉴于超极化~(13)C-MRS正在许多疾病的患者中进行积极的研究， 这一高风险/高回报项目的成功完成有可能提供一种非侵入性方法 用于GBM患者的诊断、监测和治疗评估。

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.