Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
Samsung Biomedical Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
Gynecol Oncol. 2021 Jul;162(1):173-181. doi: 10.1016/j.ygyno.2021.04.028. Epub 2021 May 7.
The patient-derived xenograft (PDX) model is a promising translational platform for duplicating the characteristics of primary tumors. Here, we established and characterized PDX models of uterine cancer to demonstrate their utility for preclinical drug testing.
We generated PDX tumors surgically derived from 58 cases of uterine cancer. Subrenal capsule xenografts and primary tumors were compared using microscopic examination, short tandem repeat analyses, and targeted sequencing analyses. A phosphatidylinositol 3-kinase (PI3K) inhibitor was administered to mice whose PDX tumors harbored a PTEN deletion or PIK3CA mutation. We also generated an orthotopic PDX model using uterine horn implantation.
Thirty-three (56.9%) PDXs were successfully generated and passaged to maintain tumors. The histological features of the PDX tumors were stable over subsequent passages. By contrast, the proportions of epithelial and mesenchymal components of carcinosarcoma PDX models varied by generation. Targeted sequencing analyses revealed that all mutated cancer-related genes were stable during establishment and subgrafting. Treatment with a PI3K inhibitor cased a significant decrease in tumor weight in the clear cell carcinoma PDX harboring a frameshift PTEN deletion (p = 0.049) and in the serous carcinoma PDX harboring a missense PI3KCA mutation (p = 0.003) compared with matched controls. We also successfully established orthotopic PDX models (3/3; 100.0%).
The histological and genetic features of PDXs were similar to those of primary tumors. This model is a promising translational platform for preclinical testing of new anticancer drugs and will enable the personalized development of therapeutic options for uterine cancer.
患者来源的异种移植（PDX）模型是一种有前途的转化平台，可以复制原发性肿瘤的特征。在这里，我们建立和表征了子宫癌的 PDX 模型，以证明它们在临床前药物测试中的应用。
我们通过手术从 58 例子宫癌患者中生成了 PDX 肿瘤。通过显微镜检查、短串联重复分析和靶向测序分析比较了肾包膜下异种移植和原发性肿瘤。对携带 PTEN 缺失或 PIK3CA 突变的 PDX 肿瘤的小鼠给予了磷脂酰肌醇 3-激酶（PI3K）抑制剂。我们还通过子宫角植入生成了一个原位 PDX 模型。
33 例（56.9%）PDX 成功生成并传代以维持肿瘤。PDX 肿瘤的组织学特征在随后的传代中保持稳定。相比之下，癌肉瘤 PDX 模型的上皮和间充质成分的比例因代际而异。靶向测序分析显示，所有突变的癌症相关基因在建立和亚移植过程中都是稳定的。与匹配对照相比，携带错义 PI3KCA 突变的浆液性癌 PDX（p=0.003）和携带移码 PTEN 缺失的透明细胞癌 PDX（p=0.049）用 PI3K 抑制剂治疗导致肿瘤重量显著减少。我们还成功建立了原位 PDX 模型（3/3；100.0%）。
PDX 的组织学和遗传特征与原发性肿瘤相似。该模型是临床前测试新抗癌药物的有前途的转化平台，并将为子宫癌的个体化治疗方案的发展提供支持。
