Molecular Imaging Program at Stanford, Bio-X Program, Department of Radiology, Stanford University, Stanford, CA, USA.
Neoplasia. 2011 Mar;13(3):266-75. doi: 10.1593/neo.101466.
Positron emission tomography (PET) imaging has become a useful tool for assessing early biologic response to cancer therapy and may be particularly useful in the development of new cancer therapeutics. RAF265, a novel B-Raf/vascular endothelial growth factor receptor-2 inhibitor, was evaluated in the preclinical setting for its ability to inhibit the uptake of PET tracers in the A375M(B-Raf(V600E)) human melanoma cell line. RAF265 inhibited 2-deoxy-2-[(18)F]fluoro-d-glucose (FDG) accumulation in cell culture at 28 hours in a dose-dependent manner. RAF265 also inhibited FDG accumulation in tumor xenografts after 1 day of drug treatment. This decrease persisted for the remaining 2 weeks of treatment. DNA microarray analysis of treated tumor xenografts revealed significantly decreased expression of genes regulating glucose and thymidine metabolism and revealed changes in apoptotic genes, suggesting that the imaging tracers FDG, 3-deoxy-3-[(18)F]fluorothymidine, and annexin V could serve as potential imaging biomarkers for RAF265 therapy monitoring. We concluded that RAF265 is highly efficacious in this xenograft model of human melanoma and decreases glucose metabolism as measured by DNA microarray analysis, cell culture assays, and small animal FDG PET scans as early as 1 day after treatment. Our results support the use of FDG PET in clinical trials with RAF265 to assess early tumor response. DNA microarray analysis and small animal PET studies may be used as complementary technologies in drug development. DNA microarray analysis allows for analysis of drug effects on multiple pathways linked to cancer and can suggest corresponding imaging tracers for further analysis as biomarkers of tumor response.
正电子发射断层扫描（PET）成像已成为评估癌症治疗早期生物学反应的有用工具，并且在新的癌症治疗药物的开发中可能特别有用。 RAF265 是一种新型的 B-Raf/血管内皮生长因子受体-2 抑制剂，在临床前研究中评估了其抑制 A375M（B-Raf（V600E））人黑色素瘤细胞系中 PET 示踪剂摄取的能力。 RAF265 以剂量依赖性方式在 28 小时的细胞培养中抑制 2-脱氧-2-[(18)F]氟-D-葡萄糖（FDG）的积累。 RAF265 还抑制了药物治疗后 1 天肿瘤异种移植物中 FDG 的积累。这种减少持续了治疗的其余 2 周。用 RAF265 治疗的肿瘤异种移植物的 DNA 微阵列分析显示，调节葡萄糖和胸苷代谢的基因的表达显著降低，并显示凋亡基因的变化，表明成像示踪剂 FDG、3-脱氧-3-[(18)F]氟胸苷和膜联蛋白 V 可作为 RAF265 治疗监测的潜在成像生物标志物。我们得出结论， RAF265 在这种人黑色素瘤异种移植模型中非常有效，并且通过 DNA 微阵列分析、细胞培养测定和小动物 FDG PET 扫描测量，在治疗后 1 天即可测量到葡萄糖代谢降低。我们的结果支持在 RAF265 的临床试验中使用 FDG PET 来评估早期肿瘤反应。DNA 微阵列分析和小动物 PET 研究可作为药物开发中的互补技术。DNA 微阵列分析允许分析药物对与癌症相关的多个途径的影响，并可建议相应的成像示踪剂进行进一步分析，作为肿瘤反应的生物标志物。
