We investigated the potential use of [¹⁸F]FDG PET as a response biomarker for PI3K pathway targeting therapies in two HER-2-overexpressing cancer models. Methods. CD-1 nude mice were inoculated with HER-2-overexpressing JIMT1 (trastuzumab-resistant) or SKOV3 (trastuzumab-sensitive) human cancer cells. Animals were treated with trastuzumab, everolimus (mTOR inhibitor), PIK90 (PI3K inhibitor), saline, or combination therapy. [¹⁸F]FDG scans were performed at baseline, two, and seven days after the start of the therapy. Tumors were delineated on CT images and relative tumor volumes (RTV) and maximum standardized uptake value (SUV_max) were calculated. Levels of pS6 and pAkt on protein tumor lysates were determined with ELISA. Results. In the SKOV3 xenografts, all treatment schedules resulted in a gradual decrease in RTV and delta SUV_max (ΔSUV_max). For all treatments combined, ΔSUV_max after 2 days was predictive for RTV after 7 days (, ). In JIMT1 tumors, monotherapy with everolimus or PIK90 resulted in a decrease in RTV ( and , respectively) and ΔSUV_max ( and , respectively) after 7 days of treatment, but not earlier, while trastuzumab resulted in nonsignificant increases compared to control. Combination therapies resulted in RTV and ΔSUV_max decrease already at day 2, except for trastuzumab+everolimus, where an early flare was observed. For all treatments combined, ΔSUV_max after 2 days was predictive for RTV after 7 days (, ), but the correlation could be improved when combination with everolimus (, ) or trastuzumab (, ) was excluded. Conclusion. Reduction in [¹⁸F]FDG after 2 days correlated with tumor volume changes after 7 days of treatment and confirms the use of [¹⁸F]FDG PET as an early response biomarker. Treatment response can however be underestimated in schedules containing trastuzumab or everolimus due to temporary increased [¹⁸F]FDG uptake secondary to negative feedback loop and crosstalk between different pathways.

中文翻译：

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[18F]FDG 摄取的早期变化作为 HER-2 阳性癌症异种移植物中 PI3K/Akt/mTOR 靶向药物的读数

我们研究了 [ ¹⁸ F]FDG PET 在两种过表达 HER-2 的癌症模型中作为 PI3K 通路靶向治疗的反应生物标志物的潜在用途。方法。CD-1 裸鼠接种过表达 HER-2 的 JIMT1（曲妥珠单抗抗性）或 SKOV3（曲妥珠单抗敏感）人类癌细胞。用曲妥珠单抗、依维莫司（mTOR 抑制剂）、PIK90（PI3K 抑制剂）、盐水或联合疗法治疗动物。[ ¹⁸ F]FDG 扫描在治疗开始后的基线、2 天和 7 天进行。在 CT 图像上描绘肿瘤并计算相对肿瘤体积 (RTV) 和最大标准化摄取值 (SUV _max )。用 ELISA 测定蛋白质肿瘤裂解物中 pS6 和 pAkt 的水平。结果。在 SKOV3 异种移植物中，所有治疗方案均导致 RTV 和 delta SUV _max ( Δ SUV _max ) 逐渐降低。对于所有联合治疗， 2 天后的Δ SUV _max可预测 7 天后的 RTV（, ）。在 JIMT1 肿瘤中，依维莫司或 PIK90 单药治疗导致 RTV 降低（和,分别) 和Δ SUV _max (和,分别) 治疗 7 天后，但不是更早，而曲妥珠单抗与对照相比没有显着增加。联合治疗在第 2 天就已经导致 RTV 和Δ SUV _max下降，但观察到早期发作的曲妥珠单抗+依维莫司除外。对于所有联合治疗， 2 天后的Δ SUV _max可预测 7 天后的 RTV（, )，但与依维莫司联合使用时，相关性可能会得到改善 (, )或曲妥珠单抗 (, )被排除在外。结论。2 天后[ ¹⁸ F]FDG 的减少与治疗 7 天后的肿瘤体积变化相关，并证实了 [ ¹⁸ F]FDG PET 作为早期反应生物标志物的使用。然而，在包含曲妥珠单抗或依维莫司的方案中，治疗反应可能被低估，因为负反馈回路和不同途径之间的串扰^{导致[ 18} F]FDG 摄取暂时增加