Next gen RNA sequencing of canine hemangiosarcoma. Canis lupus familiaris

Transcriptome analysis of hemangiosarcoma samples were performed to assess EGFR and PLAUR/uPAR expression profiles and compare to human tumors from TCGA. Abstract Sarcomas differ from carcinomas in their mesenchymal origin. Therapeutic advancements have come slowly so alternative drugs and models are urgently needed. These studies report a new drug for sarcomas that simultaneously targets both tumor and tumor neovasculature. eBAT is a bispecific angiotoxin consisting of truncated, deimmunized Pseudomonas exotoxin fused to epidermal growth factor (EGF) and the amino terminal fragment (ATF) of urokinase. Here, we study the drug in an in vivo “ontarget” companion dog trial since eBAT effectively kills canine hemangiosarcoma (HSA) and human sarcoma cells in vitro. We reasoned the model has value due to the common occurrence of spontaneous sarcomas in dogs and a limited lifespan allowing for rapid accrual and data collection. Splenectomized dogs with minimal residual disease were given one cycle of eBAT followed by adjuvant doxorubicin in an adaptive dose-finding, phase I- II study of 23 dogs with spontaneous, stage I-II, splenic HSA. eBAT improved 6-month survival from 450 days. eBAT abated expected toxicity associated with EGFR-targeting, a finding supported by mouse studies. Urokinase plasminogen activator receptor (uPAR) and EGFR are targets for human sarcomas, so thorough evaluation is crucial for validation of the dog model. Thus, we validated these markers for human sarcoma targeting in the study of 212 human and 97 canine sarcoma samples. Our results support further translation of eBAT for human patients with sarcomas and perhaps other EGFR-expressing malignancies. Overall design: Dog hemangiosarcomas sequenced using HiSeq 2000

本研究对血管肉瘤样本开展转录组分析，以评估表皮生长因子受体（EGFR）、纤溶酶原激活物受体（PLAUR/uPAR）的表达谱，并与癌症基因组图谱（TCGA）中的人类肿瘤数据进行对比。【摘要】肉瘤因其间叶组织起源而与癌相区别。肉瘤的治疗进展缓慢，因此亟需开发新型治疗药物与研究模型。本研究报道了一种可同时靶向肿瘤实体与肿瘤新生血管的抗肉瘤新型药物eBAT：该双特异性血管毒素由截短且去免疫原性的铜绿假单胞菌外毒素，分别与表皮生长因子（EGF）及尿激酶氨基末端片段（ATF）融合而成。鉴于eBAT在体外可有效杀伤犬血管肉瘤（HSA）与人类肉瘤细胞，本研究通过体内“靶向”伴侣犬试验对该药物进行评估。研究认为该模型具有重要研究价值：犬类自发性肉瘤发病率较高，且犬寿命有限，可快速完成受试者招募与数据收集。本研究纳入23例患有自发性I-II期脾脏血管肉瘤的犬只，对存在微小残留病灶的脾切除术后犬给予1个周期的eBAT治疗，随后辅以多柔比星（doxorubicin）辅助治疗，此项试验为适应性剂量探索的I-II期临床研究。eBAT可将6个月生存率提升至450天。eBAT可减轻EGFR靶向治疗相关的预期毒性，这一结论得到了小鼠试验的验证。纤溶酶原激活物受体（uPAR）与EGFR均为人类肉瘤的治疗靶点，因此对其进行全面评估对于验证犬类模型的有效性至关重要。因此，本研究通过对212例人类肉瘤样本及97例犬类肉瘤样本的分析，验证了上述可用于人类肉瘤靶向治疗的生物标志物。本研究结果为eBAT进一步转化应用于肉瘤患者及其他表达EGFR的恶性肿瘤患者提供了支持。整体实验设计：采用HiSeq 2000对犬血管肉瘤样本进行测序。