Glaser Gretchen, Weroha S John, Becker Marc A, Hou Xiaonan, Enderica-Gonzalez Sergio, Harrington Sean C, Haluska Paul
Division of Gynecologic Surgery, Mayo Clinic, Rochester, MN, United States of America.
Department of Oncology, Mayo Clinic, Rochester, MN, United States of America.
PLoS One. 2015 May 11;10(5):e0126867. doi: 10.1371/journal.pone.0126867. eCollection 2015.
Ovarian carcinosarcoma is a rare subtype of ovarian cancer with poor clinical outcomes. The low incidence of this disease makes accrual to large clinical trials challenging. However, studies have shown that treatment responses in patient-derived xenograft (PDX) models correlate with matched-patient responses in the clinic, supporting their use for preclinical testing of standard and novel therapies. An ovarian carcinosarcoma PDX is presented herein and showed resistance to carboplatin and paclitaxel (similar to the patient) but exhibited significant sensitivity to ifosfamide and paclitaxel. The PDX demonstrated overexpression of EGFR mRNA and gene amplification by array comparative genomic hybridization (log2 ratio 0.399). EGFR phosphorylation was also detected. Angiogensis and insulin-like growth factor pathways were also implicated by overexpression of VEGFC and IRS1. In order to improve response to chemotherapy, the PDX was treated with carboplatin/paclitaxel with or without a pan-HER and VEGF inhibitor (BMS-690514) but there was no tumor growth inhibition or improved animal survival, which may be explained by a KRAS mutation. Resistance was also observed when the IGF-1R inhibitor BMS-754807 was combined with carboplatin/paclitaxel. Because poly (ADP-ribose) polymerase inhibitors have activity in ovarian cancer patients, with and without BRCA mutations, ABT-888 was also tested but found to have no activity. Pathogenic mutations were also detected in TP53 and PIK3CA. In conclusion, ifosfamide/paclitaxel was superior to carboplatin/paclitaxel in this ovarian carcinosarcoma PDX and gene overexpression or amplification alone was not sufficient to predict response to targeted therapy. Better predictive markers of response are needed.
卵巢癌肉瘤是卵巢癌的一种罕见亚型，临床预后较差。该疾病发病率低，使得入组大型临床试验具有挑战性。然而，研究表明，患者来源的异种移植（PDX）模型中的治疗反应与临床中匹配患者的反应相关，支持将其用于标准疗法和新疗法的临床前测试。本文展示了一个卵巢癌肉瘤PDX，其对卡铂和紫杉醇耐药（与患者情况相似）但对异环磷酰胺和紫杉醇表现出显著敏感性。该PDX通过阵列比较基因组杂交显示EGFR mRNA过表达和基因扩增（log2比值0.399）。还检测到了EGFR磷酸化。VEGFC和IRS1的过表达也表明血管生成和胰岛素样生长因子途径参与其中。为了提高对化疗的反应，该PDX接受了卡铂/紫杉醇联合或不联合泛HER和VEGF抑制剂（BMS - 690514）的治疗，但没有肿瘤生长抑制或改善动物生存情况，这可能由KRAS突变来解释。当IGF - 1R抑制剂BMS - 754807与卡铂/紫杉醇联合使用时也观察到了耐药性。由于聚（ADP -核糖）聚合酶抑制剂在有或没有BRCA突变的卵巢癌患者中均有活性，因此也对ABT - 888进行了测试，但发现其无活性。在TP53和PIK3CA中也检测到了致病突变。总之，在这个卵巢癌肉瘤PDX中，异环磷酰胺/紫杉醇优于卡铂/紫杉醇，单独的基因过表达或扩增不足以预测对靶向治疗的反应。需要更好的反应预测标志物。
