Division of Cancer Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
J Nucl Med. 2011 Aug;52(8):1261-7. doi: 10.2967/jnumed.110.086967. Epub 2011 Jul 15.
The ability of PET to image functional changes in tumors is increasingly being used to evaluate response and predict clinical benefit to conventional and novel cancer therapies. Although the use of (18)F-FDG PET is well established, 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) PET has potential advantages as a more specific marker of cellular proliferation. c-MET signaling is frequently dysregulated in cancer and is therefore an attractive therapeutic target. Crizotinib (PF-2341066) is a novel adenosine triphosphate-competitive c-MET kinase inhibitor with antitumor activity in a range of tumor models. The aim of this study was to investigate the utility of PET of glucose metabolism and cell proliferation to monitor tumor response to crizotinib in 2 cell lines with aberrant c-MET signaling.
Mice bearing GTL-16 or U87MG xenografts were evaluated for changes in tumor volume and (18)F-FDG and (18)F-FLT uptake after daily oral treatment with up to 50 mg/kg crizotinib. GTL-16 and U87MG cells were treated with crizotinib in vitro and analyzed for (3)H-2-deoxyglucose uptake and expression of activated MET, AKT, and ERK by immunoblotting.
Treatment of c-MET-amplified GTL-16 xenografts with 50 mg/kg crizotinib caused tumor regression that was associated with a slow reduction in (18)F-FDG uptake (P < 0.05, day 13) and reduced expression of the glucose transporter 1, GLUT-1. Although baseline (18)F-FDG uptake into U87MG tumors was substantially higher than in GTL-16 tumors, (18)F-FDG uptake into U87MG tumors remained unchanged on treatment at 50 mg/kg crizotinib, despite tumor growth inhibition of 93% on day 8 of treatment. These findings were confirmed in vitro, where treatment of U87MG cells with 1 μM crizotinib had no demonstrable effect on glucose uptake. Furthermore, these cells demonstrated constitutive, crizotinib-independent phosphoinositide 3-kinase pathway signaling as demonstrated by phosphorylated AKT and ribosomal protein S6. Both U87MG and GTL-16 tumors showed high baseline uptake of (18)F-FLT, which was reduced by 50% and 53% on days 4 and 8 of treatment, respectively.
While the results provide a strong rationale to investigate the use of (18)F-FLT PET as a clinical biomarker for monitoring tumor response to c-MET inhibition, (18)F-FDG PET may be a less robust marker.
研究葡萄糖代谢和细胞增殖 PET 监测异常 c-MET 信号传导的 2 种细胞系对克唑替尼肿瘤反应的作用。
在每日口服高达 50mg/kg 克唑替尼后，用 GTL-16 或 U87MG 异种移植瘤评估肿瘤体积和 18 F-FDG 和 18 F-FLT 摄取的变化。体外用克唑替尼处理 GTL-16 和 U87MG 细胞，并用免疫印迹法分析 3 H-2-脱氧葡萄糖摄取和激活 MET、AKT 和 ERK 的表达。
50mg/kg 克唑替尼治疗 c-MET 扩增的 GTL-16 异种移植瘤导致肿瘤消退，与 18 F-FDG 摄取缓慢减少（P<0.05，第 13 天）和葡萄糖转运蛋白 1（GLUT-1）表达降低有关。尽管 U87MG 肿瘤的基线 18 F-FDG 摄取量明显高于 GTL-16 肿瘤，但在 50mg/kg 克唑替尼治疗时 U87MG 肿瘤的 18 F-FDG 摄取量保持不变，尽管在治疗的第 8 天肿瘤生长抑制了 93%。这些发现得到了体外研究的证实，其中 1μM 克唑替尼处理 U87MG 细胞对葡萄糖摄取没有明显影响。此外，这些细胞表现出组成型、克唑替尼独立的磷酸肌醇 3-激酶途径信号传导，如磷酸化 AKT 和核糖体蛋白 S6 所示。U87MG 和 GTL-16 肿瘤在基线时摄取大量的 18 F-FLT，分别在治疗的第 4 天和第 8 天减少了 50%和 53%。
虽然结果为研究 18 F-FLT PET 作为监测 c-MET 抑制肿瘤反应的临床生物标志物提供了强有力的依据，但 18 F-FDG PET 可能是一种不太可靠的标志物。
