FLT-PET监测靶向治疗ALK阳性淋巴瘤早期疗效优于FDG-PET
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摘要
复发的侵袭性淋巴瘤一般预后较差,靶向药物治疗成为当今肿瘤学研究的热点。准确指示癌症对治疗早期反应的影像学方法会大大提高对靶向药物治疗的效率。使用各种ALK阳性间变性大细胞淋巴瘤(ALCL)细胞系来评估靶向药物(HSP90抑制剂NVP-AUY922和m TOR抑制剂癌伏妥)的早期疗效,两者都显示出具有干扰ALK依赖性致癌信号转导的功能。细胞实验中使用MTT、示踪剂摄取及其他生化试验来分析ALK诱导的信号传导。另外,对ALCL异种移植物小鼠行FDG和FLT-PET,评估NVP-AUY922或依维莫司在体内的早期治疗反应。结果显示SUDHL-1细胞对两种抑制剂的干预敏感;早在治疗开始5 h时FLT摄取就有明显降低。病理检测显示Ki-67表达减少,而caspase-3的表达增加。但FDG摄取在治疗早期无显著变化。Karpas299细胞对NVP-AUY922的治疗具有抗性,对依维莫司治疗敏感。在施用治疗后第2天NVP-AUY299干预组的FLT摄取依旧增加,癌伏妥治疗组的FLT摄取显著降低。FLT-PET能在靶向治疗早期就预测淋巴瘤对治疗的反应,对早期疗效的预测FDG-PET比FLT-PET略差。
The prognosis of relapsed or refractory aggressive lymphoma is poor. The huge variety of currently evolving targeted treatment approaches would benefit from tools for early prediction of response or resistance. We used various ALK-positive anaplastic large cell lymphoma(ALCL) cell lines to evaluate two inhibitors, the HSP90 inhibitor NVP-AUY922, and the mTOR inhibitor everolimus, both of which have shown to interfere with ALK-dependent oncogenic signal transduction. Their therapeutic effect was determined in vitro by MTT assay, [18 F]fluorodeoxyglucose(FDG)-and [18 F]fluorothymidine(FLT)-uptake, and by biochemical analysis of ALK-induced signaling. Micro-FDG-and FLT-positron emission tomography(PET) imaging studies in immunodeficient mice bearing ALCL xenotransplants were carried out with the cell lines SUDHL-1 and Karpas299 to assess early treatment response to NVP-AUY922 or everolimus in vivo. SUDHL-1 cells showed sensitivity to both inhibitors in vitro. Importantly, we detected a significant reduction of FLT-uptake in SUDHL-1 bearing animals using both inhibitors compared with baseline as early as 5 days after initiation of targeted therapy. Immunostaining showed a decrease in Ki-67 and an increase in cleaved caspase-3 staining. In contrast, FDG-uptake did not significantly decrease at early time points. Karpas299 xenotransplants, which are resistant to NVP-AUY922 and sensitive to everolimus treatment, showed an increase of mean FLT-uptake on day 2 after administration of NVP-AUY299, but a significant reduction in FLT-uptake upon everolimus treatment. In conclusion, we show that FLT-PET but not FDGPET is able to predict response to treatment with specific inhibitors very early in the course of treatment and thus enables early prediction of treatment efficacy.
The prognosis of relapsed or refractory aggressive lymphoma is poor. The huge variety of currently evolving targeted treatment approaches would benefit from tools for early prediction of response or resistance. We used various ALK-positive anaplastic large cell lymphoma(ALCL) cell lines to evaluate two inhibitors, the HSP90 inhibitor NVP-AUY922, and the mTOR inhibitor everolimus, both of which have shown to interfere with ALK-dependent oncogenic signal transduction. Their therapeutic effect was determined in vitro by MTT assay, [18 F]fluorodeoxyglucose(FDG)-and [18 F]fluorothymidine(FLT)-uptake, and by biochemical analysis of ALK-induced signaling. Micro-FDG-and FLT-positron emission tomography(PET) imaging studies in immunodeficient mice bearing ALCL xenotransplants were carried out with the cell lines SUDHL-1 and Karpas299 to assess early treatment response to NVP-AUY922 or everolimus in vivo. SUDHL-1 cells showed sensitivity to both inhibitors in vitro. Importantly, we detected a significant reduction of FLT-uptake in SUDHL-1 bearing animals using both inhibitors compared with baseline as early as 5 days after initiation of targeted therapy. Immunostaining showed a decrease in Ki-67 and an increase in cleaved caspase-3 staining. In contrast, FDG-uptake did not significantly decrease at early time points. Karpas299 xenotransplants, which are resistant to NVP-AUY922 and sensitive to everolimus treatment, showed an increase of mean FLT-uptake on day 2 after administration of NVP-AUY299, but a significant reduction in FLT-uptake upon everolimus treatment. In conclusion, we show that FLT-PET but not FDGPET is able to predict response to treatment with specific inhibitors very early in the course of treatment and thus enables early prediction of treatment efficacy.
引文