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...
| Main Authors: | , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-09-01
|
| Series: | Molecular Therapy: Oncolytics |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S237277052300061X |
| _version_ | 1797733094271221760 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Amos Hong Pheng Loh |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T12:24:09Z |
| format | Article |
| id | doaj.art-de65b776c23d4d7cb7d07c8b6584356a |
| institution | Directory Open Access Journal |
| issn | 2372-7705 |
| language | English |
| last_indexed | 2024-03-12T12:24:09Z |
| publishDate | 2023-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Oncolytics |
| spelling | doaj.art-de65b776c23d4d7cb7d07c8b6584356a2023-08-30T05:50:49ZengElsevierMolecular Therapy: Oncolytics2372-77052023-09-0130153166Exploiting frequent and specific expression of PRL3 in pediatric solid tumors for first-in-child use of PRL3-zumab humanized antibodyAmos Hong Pheng Loh0Min Thura1Abhishek Gupta2Sheng Hui Tan3Kelvin Kam Yew Kuan4Koon Hwee Ang5Khurshid Merchant6Kenneth Tou En Chang7Hui Yi Yon8Yong Chen9Mathew Hern Wang Cheng10Arjandas Mahadev11Matthew Chau Hsien Ng12Michaela Su-Fern Seng13Prasad Iyer14Pei Ling Chia15Shui Yen Soh16Qi Zeng17VIVA-KKH Paediatric Brain and Solid Tumour Programme, Children’s Blood and Cancer Centre, KK Women’s and Children’s Hospital Singapore 229899, Singapore; Duke-NUS School of Medicine, Singapore 169857, Singapore; Department of Paediatric Surgery, KK Women’s and Children’s Hospital, Singapore 229899, Singapore; Corresponding author: Amos Hong Pheng Loh, VIVA-KKH Paediatric Brain and Solid Tumour Programme, Children’s Blood and Cancer Centre, KK Women’s and Children’s Hospital, Singapore 229899, Singapore.Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology, and Research (A∗STAR), Singapore 138673, SingaporeInstitute of Molecular and Cell Biology (IMCB), Agency for Science, Technology, and Research (A∗STAR), Singapore 138673, SingaporeVIVA-KKH Paediatric Brain and Solid Tumour Programme, Children’s Blood and Cancer Centre, KK Women’s and Children’s Hospital Singapore 229899, SingaporeInstitute of Molecular and Cell Biology (IMCB), Agency for Science, Technology, and Research (A∗STAR), Singapore 138673, SingaporeInstitute of Molecular and Cell Biology (IMCB), Agency for Science, Technology, and Research (A∗STAR), Singapore 138673, SingaporeVIVA-KKH Paediatric Brain and Solid Tumour Programme, Children’s Blood and Cancer Centre, KK Women’s and Children’s Hospital Singapore 229899, Singapore; Duke-NUS School of Medicine, Singapore 169857, Singapore; Department of Pathology and Laboratory Medicine, KK Women’s and Children’s Hospital, Singapore 229899, SingaporeVIVA-KKH Paediatric Brain and Solid Tumour Programme, Children’s Blood and Cancer Centre, KK Women’s and Children’s Hospital Singapore 229899, Singapore; Duke-NUS School of Medicine, Singapore 169857, Singapore; Department of Pathology and Laboratory Medicine, KK Women’s and Children’s Hospital, Singapore 229899, SingaporeDepartment of Pathology and Laboratory Medicine, KK Women’s and Children’s Hospital, Singapore 229899, SingaporeDuke-NUS School of Medicine, Singapore 169857, Singapore; Department of Paediatric Surgery, KK Women’s and Children’s Hospital, Singapore 229899, SingaporeDepartment of Orthopaedic Surgery, KK Women’s and Children’s Hospital, Singapore 229899, SingaporeDuke-NUS School of Medicine, Singapore 169857, Singapore; Department of Orthopaedic Surgery, KK Women’s and Children’s Hospital, Singapore 229899, SingaporeDuke-NUS School of Medicine, Singapore 169857, Singapore; Department of GI Oncology, National Cancer Centre Singapore, Singapore 229899, SingaporeVIVA-KKH Paediatric Brain and Solid Tumour Programme, Children’s Blood and Cancer Centre, KK Women’s and Children’s Hospital Singapore 229899, Singapore; Duke-NUS School of Medicine, Singapore 169857, Singapore; Department of Paediatric Subspecialties Haematology/Oncology Service, KK Women’s and Children’s Hospital, Singapore 229899, SingaporeVIVA-KKH Paediatric Brain and Solid Tumour Programme, Children’s Blood and Cancer Centre, KK Women’s and Children’s Hospital Singapore 229899, Singapore; Duke-NUS School of Medicine, Singapore 169857, Singapore; Department of Paediatric Subspecialties Haematology/Oncology Service, KK Women’s and Children’s Hospital, Singapore 229899, SingaporeInstitute of Molecular and Cell Biology (IMCB), Agency for Science, Technology, and Research (A∗STAR), Singapore 138673, SingaporeVIVA-KKH Paediatric Brain and Solid Tumour Programme, Children’s Blood and Cancer Centre, KK Women’s and Children’s Hospital Singapore 229899, Singapore; Duke-NUS School of Medicine, Singapore 169857, Singapore; Department of Paediatric Subspecialties Haematology/Oncology Service, KK Women’s and Children’s Hospital, Singapore 229899, SingaporeInstitute of Molecular and Cell Biology (IMCB), Agency for Science, Technology, and Research (A∗STAR), Singapore 138673, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119260, Singapore; Corresponding author: Qi Zeng, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology, and Research (A∗STAR), Singapore 138673, Singapore.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.http://www.sciencedirect.com/science/article/pii/S237277052300061XPRL3PTP4A3, PRL3-zumabpediatric tumorsneuroblastomarhabdomyosarcomanon-rhabdomyosarcoma soft tissue sarcoma |
| spellingShingle | 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 Exploiting frequent and specific expression of PRL3 in pediatric solid tumors for first-in-child use of PRL3-zumab humanized antibody Molecular Therapy: Oncolytics PRL3 PTP4A3, PRL3-zumab pediatric tumors neuroblastoma rhabdomyosarcoma non-rhabdomyosarcoma soft tissue sarcoma |
| title | Exploiting frequent and specific expression of PRL3 in pediatric solid tumors for first-in-child use of PRL3-zumab humanized antibody |
| title_full | Exploiting frequent and specific expression of PRL3 in pediatric solid tumors for first-in-child use of PRL3-zumab humanized antibody |
| title_fullStr | Exploiting frequent and specific expression of PRL3 in pediatric solid tumors for first-in-child use of PRL3-zumab humanized antibody |
| title_full_unstemmed | Exploiting frequent and specific expression of PRL3 in pediatric solid tumors for first-in-child use of PRL3-zumab humanized antibody |
| title_short | Exploiting frequent and specific expression of PRL3 in pediatric solid tumors for first-in-child use of PRL3-zumab humanized antibody |
| title_sort | exploiting frequent and specific expression of prl3 in pediatric solid tumors for first in child use of prl3 zumab humanized antibody |
| topic | PRL3 PTP4A3, PRL3-zumab pediatric tumors neuroblastoma rhabdomyosarcoma non-rhabdomyosarcoma soft tissue sarcoma |
| url | http://www.sciencedirect.com/science/article/pii/S237277052300061X |
| work_keys_str_mv | AT amoshongphengloh exploitingfrequentandspecificexpressionofprl3inpediatricsolidtumorsforfirstinchilduseofprl3zumabhumanizedantibody AT minthura exploitingfrequentandspecificexpressionofprl3inpediatricsolidtumorsforfirstinchilduseofprl3zumabhumanizedantibody AT abhishekgupta exploitingfrequentandspecificexpressionofprl3inpediatricsolidtumorsforfirstinchilduseofprl3zumabhumanizedantibody AT shenghuitan exploitingfrequentandspecificexpressionofprl3inpediatricsolidtumorsforfirstinchilduseofprl3zumabhumanizedantibody AT kelvinkamyewkuan exploitingfrequentandspecificexpressionofprl3inpediatricsolidtumorsforfirstinchilduseofprl3zumabhumanizedantibody AT koonhweeang exploitingfrequentandspecificexpressionofprl3inpediatricsolidtumorsforfirstinchilduseofprl3zumabhumanizedantibody AT khurshidmerchant exploitingfrequentandspecificexpressionofprl3inpediatricsolidtumorsforfirstinchilduseofprl3zumabhumanizedantibody AT kennethtouenchang exploitingfrequentandspecificexpressionofprl3inpediatricsolidtumorsforfirstinchilduseofprl3zumabhumanizedantibody AT huiyiyon exploitingfrequentandspecificexpressionofprl3inpediatricsolidtumorsforfirstinchilduseofprl3zumabhumanizedantibody AT yongchen exploitingfrequentandspecificexpressionofprl3inpediatricsolidtumorsforfirstinchilduseofprl3zumabhumanizedantibody AT mathewhernwangcheng exploitingfrequentandspecificexpressionofprl3inpediatricsolidtumorsforfirstinchilduseofprl3zumabhumanizedantibody AT arjandasmahadev exploitingfrequentandspecificexpressionofprl3inpediatricsolidtumorsforfirstinchilduseofprl3zumabhumanizedantibody AT matthewchauhsienng exploitingfrequentandspecificexpressionofprl3inpediatricsolidtumorsforfirstinchilduseofprl3zumabhumanizedantibody AT michaelasufernseng exploitingfrequentandspecificexpressionofprl3inpediatricsolidtumorsforfirstinchilduseofprl3zumabhumanizedantibody AT prasadiyer exploitingfrequentandspecificexpressionofprl3inpediatricsolidtumorsforfirstinchilduseofprl3zumabhumanizedantibody AT peilingchia exploitingfrequentandspecificexpressionofprl3inpediatricsolidtumorsforfirstinchilduseofprl3zumabhumanizedantibody AT shuiyensoh exploitingfrequentandspecificexpressionofprl3inpediatricsolidtumorsforfirstinchilduseofprl3zumabhumanizedantibody AT qizeng exploitingfrequentandspecificexpressionofprl3inpediatricsolidtumorsforfirstinchilduseofprl3zumabhumanizedantibody |