Laws Maxwell T, Bonomi Robin E, Gelovani David J, Llaniguez Jeremy, Lu Xin, Mangner Thomas, Gelovani Juri G
Department of Biomedical Engineering, College of Engineering and School of Medicine, Wayne State University, Detroit, Michigan, USA.
Positron Emission Tomography Center, Wayne State University, Detroit, Michigan, USA.
Neurooncol Adv. 2020 Jan-Dec;2(1):vdaa006. doi: 10.1093/noajnl/vdaa006. Epub 2020 Jan 16.
Several studies demonstrated that glioblastoma multiforme progression and recurrence is linked to epigenetic regulatory mechanisms. Sirtuin 1 (SIRT1) plays an important role in glioma progression, invasion, and treatment response and is a potential therapeutic target. The aim of this study is to test the feasibility of 2-[F]BzAHA for quantitative imaging of SIRT1 expression-activity and monitoring pharmacologic inhibition in a rat model of intracerebral glioma.
Sprague Dawley rats bearing 9L ( = 12) intracerebral gliomas were injected with 2-[F]BzAHA (300-500 µCi/animal i.v.) and dynamic positron-emission tomography (PET) imaging was performed for 60 min. Then, SIRT1 expression in 9L tumors ( = 6) was studied by immunofluorescence microscopy (IF). Two days later, rats with 9L gliomas were treated either with SIRT1 specific inhibitor EX-527 (5 mg/kg, i.p.; = 3) or with histone deacetylases class IIa specific inhibitor MC1568 (30 mg/kg, i.p.; = 3) and 30 min later were injected i.v. with 2-[F]BzAHA. PET-computerized tomography-magnetic resonance (PET/CT/MR) images acquired after EX-527 and MC1568 treatments were co-registered with baseline images.
Standard uptake values (SUVs) of 2-[F]BzAHA in 9L tumors measured at 20 min post-radiotracer administration were 1.11 ± 0.058 and had a tumor-to-brainstem SUV ratio of 2.73 ± 0.141. IF of 9L gliomas revealed heterogeneous upregulation of SIRT1, especially in hypoxic and peri-necrotic regions. Significant reduction in 2-[F]BzAHA SUV and distribution volume in 9L tumors was observed after administration of EX-527, but not MC1568.
PET/CT/MRI with 2-[F]BzAHA can facilitate studies to elucidate the roles of SIRT1 in gliomagenesis and progression, as well as to optimize therapeutic doses of novel SIRT1 inhibitors.
多项研究表明，多形性胶质母细胞瘤的进展和复发与表观遗传调控机制有关。沉默调节蛋白1（SIRT1）在胶质瘤的进展、侵袭及治疗反应中起重要作用，是一个潜在的治疗靶点。本研究旨在测试2-[F]BzAHA在大鼠脑胶质瘤模型中对SIRT1表达活性进行定量成像及监测药物抑制作用的可行性。
给12只荷9L脑胶质瘤的Sprague Dawley大鼠静脉注射2-[F]BzAHA（300 - 500 μCi/只），并进行60分钟的动态正电子发射断层扫描（PET）成像。然后，通过免疫荧光显微镜（IF）研究6只9L肿瘤中SIRT1的表达。两天后，给荷9L胶质瘤的大鼠分别用SIRT1特异性抑制剂EX - 527（5 mg/kg，腹腔注射；3只）或IIa类组蛋白去乙酰化酶特异性抑制剂MC1568（30 mg/kg，腹腔注射；3只）治疗，30分钟后静脉注射2-[F]BzAHA。将EX - 527和MC1568治疗后获得的PET - 计算机断层扫描 - 磁共振（PET/CT/MR）图像与基线图像进行配准。
放射性示踪剂给药后20分钟测量的9L肿瘤中2-[F]BzAHA的标准摄取值（SUVs）为1.11±0.058，肿瘤与脑干的SUV比值为2.73±0.141。9L胶质瘤的IF显示SIRT1异质性上调，尤其是在缺氧和坏死周边区域。给予EX - 527后，观察到9L肿瘤中2-[F]BzAHA的SUV和分布容积显著降低，但给予MC1568后未观察到。
使用2-[F]BzAHA的PET/CT/MRI有助于阐明SIRT1在胶质瘤发生和进展中的作用，并优化新型SIRT1抑制剂的治疗剂量。
