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

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

Molecular Therapy - Oncology

10.1016/j.omto.2023.08.006

http://dx.doi.org/10.1016/j.omto.2023.08.006

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

PRL3 PTP4A3, PRL3-zumab pediatric tumors neuroblastoma rhabdomyosarcoma non-rhabdomyosarcoma soft tissue sarcoma osteosarcoma Wilms tumor

18 August 2023

Loh, A. H. P., Thura, M., Gupta, A., Tan, S. H., Kuan, K. K. Y., Ang, K. H., Merchant, K., Chang, K. T. E., Yon, H. Y., Chen, Y., Cheng, M. H. W., Mahadev, A., Ng, M. C. H., Seng, M. S.-F., Iyer, P., Chia, P. L., Soh, S. Y., & Zeng, Q. (2023). Exploiting frequent and specific expression of PRL3 in pediatric solid tumors for first-in-child use of PRL3-zumab humanized antibody. Molecular Therapy - Oncolytics, 30, 153–166. https://doi.org/10.1016/j.omto.2023.08.006

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.

Attribution 4.0 International (CC BY 4.0)

This research / project is supported by the VIVA Foundation for Children with Cancer and the KKH Health Fund - VIVA-KKH Paediatric Brain and Solid Tumour Programme
Grant Reference no. : 02/FY2015/EX/06-A42

This research is supported by core funding from: Institute of Molecular and Cell Biology
Grant Reference no. :

https://oar.a-star.edu.sg/communities-collections/articles/21013

2372-7705

Institute of Molecular and Cell Biology

https://www.cell.com/action/showPdf?pii=S2372-7705%2823%2900061-X