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
{"title":"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。","authors":"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","doi":"10.1016/j.omto.2023.08.006","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":null,"pages":null},"PeriodicalIF":5.3000,"publicationDate":"2023-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10477756/pdf/","citationCount":"0","resultStr":"{\"title\":\"Exploiting frequent and specific expression of PRL3 in pediatric solid tumors for first-in-child use of PRL3-zumab humanized antibody.\",\"authors\":\"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\",\"doi\":\"10.1016/j.omto.2023.08.006\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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. 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Exploiting frequent and specific expression of PRL3 in pediatric solid tumors for first-in-child use of PRL3-zumab humanized antibody.
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.
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.