Purpose

Ovarian cancer (OC) leads to poor survival rates mainly due to late stage detection and innate or acquired resistance to chemotherapy. Thus, efforts have been made to exploit the estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) to treat OC. However, patients eventually become resistant to these treatments as well. HER2 overexpression contributes to the acquired resistance to ER-targeted treatment. Trastuzumab treatment, on the other hand, can result in increased expression of ER, which, in turn, increases the sensitivity of the tumors towards anti-estrogen therapy. More insight into the crosstalk between ER and HER2 signaling could improve our knowledge about acquired resistance in ovarian cancer. The aim of this study was to evaluate whether PET could be used to detect changes in ER expression induced by HER2-targeted treatment in vivo.

Procedures

Male athymic nude mice were subcutaneously (sc) inoculated with 10⁶ SKOV3 human ovarian cancer cells (HER2+/ER+). Two weeks after inoculation, tumor-bearing mice were treated intraperitoneally with either vehicle, the HER2 antibody trastuzumab (20 mg/kg, 2×/week), or the HER2-tyrosine kinase inhibitor lapatinib (40 mg/kg, 5 days/week) for 2 weeks. Thereafter, ER expression in the tumor was assessed by PET imaging with 16α-[¹⁸F]-fluoro-17β-estradiol ([¹⁸F]FES). Tumors were excised for ex vivo ER and HER2 measurement with Western blotting and immunohistochemistry.

Results

All treatments led to smaller tumors than vehicle-treated tumors. Higher [¹⁸F]FES maximum standardize tumor uptake (SUV_max) was observed in animals treated with trastuzumab (+ 29 %, P = 0.002) or lapatinib (+ 20 %, P = 0.096) than in vehicle-treated controls. PET results were in agreement with ex vivo analyses.

Conclusion

FES-PET imaging can detect changes in ER expression induced by HER2-targeted treatment and therefore can be used to investigate the crosstalk between ER and HER2 in a noninvasive manner.

中文翻译：

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用 PET 监测雌激素受体和人类表皮生长因子受体 2 之间的串扰。

目的

卵巢癌 (OC) 导致存活率低，主要是由于晚期检测和对化疗的先天或获得性耐药。因此，已经努力利用雌激素受体 (ER) 和人表皮生长因子受体 2 (HER2) 来治疗 OC。然而，患者最终也会对这些治疗产生抗药性。HER2 过表达导致对 ER 靶向治疗的获得性耐药。另一方面，曲妥珠单抗治疗可导致 ER 表达增加，从而增加肿瘤对抗雌激素治疗的敏感性。更深入地了解 ER 和 HER2 信号之间的串扰可以提高我们对卵巢癌获得性耐药性的了解。体内。

程序

雄性无胸腺裸鼠皮下(sc)接种10 ⁶ SKOV3人卵巢癌细胞(HER2+/ER+)。接种两周后，荷瘤小鼠用载体、HER2 抗体曲妥珠单抗（20 毫克/公斤，2×/周）或 HER2-酪氨酸激酶抑制剂拉帕替尼（40 毫克/公斤，5 天/周）进行腹膜内治疗） 2个礼拜。此后，通过使用 16α-[ ¹⁸ F]-氟-17β-雌二醇 ([ ¹⁸ F] FES)的 PET 成像评估肿瘤中的 ER 表达。切除肿瘤以使用蛋白质印迹和免疫组织化学进行离体ER 和 HER2 测量。

结果

所有治疗导致比载体治疗的肿瘤更小的肿瘤。在用曲妥珠单抗 (+ 29 %, P  = 0.002) 或拉帕替尼 (+ 20 %, P  = 0.096)治疗的动物中，观察到的[ ¹⁸ F]FES 最大标准化肿瘤摄取量 (SUV _max ) 高于媒介物治疗的对照组。PET 结果与体外分析一致。

结论

FES-PET 成像可以检测 HER2 靶向治疗诱导的 ER 表达变化，因此可用于以非侵入性方式研究 ER 和 HER2 之间的串扰。