Abstract：
OBJECTIVE: Dedifferentiated endometrial carcinoma (DDEC) characterized by SWItch/Sucrose Non-Fermentable (SWI/SNF) complex inactivation is a highly aggressive type of endometrial cancer without effective systemic therapy options. Its uncommon nature and aggressive disease trajectory pose significant challenges for therapeutic progress. To address this obstacle, we focused on developing preclinical models tailored to this tumor type and established patient tumor-derived three-dimensional (3D) spheroid models of DDEC.
METHODS: High-throughput drug repurposing screens were performed on in vitro 3D spheroid models of DDEC cell lines (SMARCA4-inactivated DDEC-1 and ARID1A/ARID1B co-inactivated DDEC-2). The dose-response relationships of the identified candidate drugs were evaluated in vitro, followed by in vivo evaluation using xenograft models of DDEC-1 and DDEC-2.
RESULTS: Drug screen in 3D models identified multiple cardiac glycosides including digoxin and digitoxin as candidate drugs in both DDEC-1 and DDEC-2. Subsequent in vitro dose-response analyses confirmed the inhibitory activity of digoxin and digitoxin with both drugs showing lower IC50 in DDEC cells compared to non-DDEC endometrial cancer cells. In in vivo xenograft models, digoxin significantly suppressed the growth of DDEC tumors at clinically relevant serum concentrations.
CONCLUSIONS: Using biologically precise preclinical models of DDEC derived from patient tumor samples, our study identified digoxin as an effective drug in suppressing DDEC tumor growth. These findings provide compelling preclinical evidence for the use of digoxin as systemic therapy for SWI/SNF-inactivated DDEC, which may also be applicable to other SWI/SNF-inactivated tumor types.
METHODS: High-throughput drug repurposing screens were performed on in vitro 3D spheroid models of DDEC cell lines (SMARCA4-inactivated DDEC-1 and ARID1A/ARID1B co-inactivated DDEC-2). The dose-response relationships of the identified candidate drugs were evaluated in vitro, followed by in vivo evaluation using xenograft models of DDEC-1 and DDEC-2.
RESULTS: Drug screen in 3D models identified multiple cardiac glycosides including digoxin and digitoxin as candidate drugs in both DDEC-1 and DDEC-2. Subsequent in vitro dose-response analyses confirmed the inhibitory activity of digoxin and digitoxin with both drugs showing lower IC50 in DDEC cells compared to non-DDEC endometrial cancer cells. In in vivo xenograft models, digoxin significantly suppressed the growth of DDEC tumors at clinically relevant serum concentrations.
CONCLUSIONS: Using biologically precise preclinical models of DDEC derived from patient tumor samples, our study identified digoxin as an effective drug in suppressing DDEC tumor growth. These findings provide compelling preclinical evidence for the use of digoxin as systemic therapy for SWI/SNF-inactivated DDEC, which may also be applicable to other SWI/SNF-inactivated tumor types.
摘要：
目的：去分化子宫内膜癌（DDEC）以SWItch/蔗糖非发酵（SWI/SNF）复合物失活为特征，是一种高度侵袭性的子宫内膜癌，没有有效的全身治疗选择。其罕见的性质和侵袭性的疾病轨迹对治疗进展提出了重大挑战。为了解决这个障碍，我们专注于开发针对该肿瘤类型的临床前模型,并建立了患者肿瘤来源的DDEC三维(3D)球体模型.
方法：在DDEC细胞系（SMARCA4灭活的DDEC-1和ARID1A/ARID1B共灭活的DDEC-2）的体外3D球体模型上进行高通量药物再利用筛选。在体外评估已确定的候选药物的剂量-反应关系，然后使用DDEC-1和DDEC-2的异种移植模型进行体内评估。
结果：在3D模型中的药物筛选确定了包括地高辛和洋地黄毒苷在内的多种强心苷作为DDEC-1和DDEC-2的候选药物。随后的体外剂量反应分析证实了地高辛和洋地黄毒苷的抑制活性，两种药物在DDEC细胞中的IC50均低于非DDEC子宫内膜癌细胞。在体内异种移植模型中，地高辛在临床相关血清浓度下显着抑制DDEC肿瘤的生长。
结论：使用来自患者肿瘤样本的DDEC的生物学精确临床前模型，我们的研究确定地高辛是抑制DDEC肿瘤生长的有效药物.这些发现为使用地高辛作为SWI/SNF灭活的DDEC的全身治疗提供了令人信服的临床前证据。这也可能适用于其他SWI/SNF灭活的肿瘤类型。
方法：在DDEC细胞系（SMARCA4灭活的DDEC-1和ARID1A/ARID1B共灭活的DDEC-2）的体外3D球体模型上进行高通量药物再利用筛选。在体外评估已确定的候选药物的剂量-反应关系，然后使用DDEC-1和DDEC-2的异种移植模型进行体内评估。
结果：在3D模型中的药物筛选确定了包括地高辛和洋地黄毒苷在内的多种强心苷作为DDEC-1和DDEC-2的候选药物。随后的体外剂量反应分析证实了地高辛和洋地黄毒苷的抑制活性，两种药物在DDEC细胞中的IC50均低于非DDEC子宫内膜癌细胞。在体内异种移植模型中，地高辛在临床相关血清浓度下显着抑制DDEC肿瘤的生长。
结论：使用来自患者肿瘤样本的DDEC的生物学精确临床前模型，我们的研究确定地高辛是抑制DDEC肿瘤生长的有效药物.这些发现为使用地高辛作为SWI/SNF灭活的DDEC的全身治疗提供了令人信服的临床前证据。这也可能适用于其他SWI/SNF灭活的肿瘤类型。
