Exploiting frequent and specific expression of PRL3 in pediatric solid tumors for first-in-child use of PRL3-zumab humanized antibody.

IF 5.3 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Amos Hong Pheng Loh, Min Thura, Abhishek Gupta, Sheng Hui Tan, Kelvin Kam Yew Kuan, Koon Hwee Ang, Khurshid Merchant, Kenneth Tou En Chang, Hui Yi Yon, Yong Chen, Mathew Hern Wang Cheng, Arjandas Mahadev, Matthew Chau Hsien Ng, Michaela Su-Fern Seng, Prasad Iyer, Pei Ling Chia, Shui Yen Soh, Qi Zeng
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Abstract

Phosphatase of regenerating liver 3 (PRL3) is a specific tumor antigen overexpressed in a broad range of adult cancer types. However, its physiological expression in pediatric embryonal and mesenchymal tumors and its association with clinical outcomes in children is unknown. We sought to profile the expression of PRL3 in pediatric tumors in relation to survival outcomes, expression of angiogenesis markers, and G-protein-coupled receptor (GPCR)-mitogen-activated protein kinase (MAPK) signaling targets. PRL3-zumab, a first-in-class humanized antibody, was administered in a dose escalation schedule in a first-in-child clinical trial to study toxicity, pharmacokinetics, and clinical outcomes. Among 64 pediatric tumors, PRL3 was most frequently expressed in neuroblastoma (100%), rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcomas (71%), and renal sarcomas (60%) but absent in paired normal tissues. PRL3 was expressed in 75% of relapsed tumors and associated with shorter median event-free survival. Microarray profiling of PRL3-positive tumors showed elevation of angiogenin, TIMP1 and TIMP2, and GPCR-MAPK signaling proteins that commonly interacted with PRL3. The first use of PRL3-zumab in a pediatric patient saw no adverse events. A 28.6% reduction in maximum target lesion diameter was achieved when PRL3-zumab was administered concurrently with hypofractionated radiation. These findings support wider exploration of PRL3 expression in embryonal and mesenchymal tumors and further clinical application of PRL3-zumab in pediatric patients.

Abstract Image

利用PRL3在儿童实体瘤中的频繁和特异性表达,首次在儿童中使用PRL3-zumab人源化抗体。
再生肝3磷酸酶(PRL3)是一种特异性肿瘤抗原,在广泛的成人癌症类型中过表达。然而,其在儿童胚胎和间充质肿瘤中的生理表达及其与儿童临床预后的关系尚不清楚。我们试图分析PRL3在儿童肿瘤中的表达与生存结局、血管生成标志物的表达以及g蛋白偶联受体(GPCR)-丝裂原活化蛋白激酶(MAPK)信号靶点的关系。PRL3-zumab是一种同类首创的人源化抗体,在一项首次在儿童中进行的临床试验中以剂量递增计划给药,以研究毒性、药代动力学和临床结果。在64个儿童肿瘤中,PRL3最常在神经母细胞瘤(100%)、横纹肌肉瘤和非横纹肌肉瘤软组织肉瘤(71%)和肾肉瘤(60%)中表达,但在成对的正常组织中不表达。PRL3在75%的复发肿瘤中表达,与较短的中位无事件生存期相关。PRL3阳性肿瘤的芯片分析显示血管生成素、TIMP1和TIMP2以及通常与PRL3相互作用的GPCR-MAPK信号蛋白升高。首次在儿科患者中使用PRL3-zumab未见不良事件。当PRL3-zumab与低分割放疗同时使用时,最大目标病变直径减少了28.6%。这些发现支持更广泛地探索PRL3在胚胎和间质肿瘤中的表达,以及PRL3-zumab在儿科患者中的进一步临床应用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Molecular Therapy Oncolytics
Molecular Therapy Oncolytics Medicine-Oncology
CiteScore
10.90
自引率
3.50%
发文量
152
审稿时长
6 weeks
期刊介绍: Molecular Therapy — Oncolytics is an international, online-only, open access journal focusing on the development and clinical testing of viral, cellular, and other biological therapies targeting cancer.
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