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

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

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

Mol Ther Oncolytics. 2023 Aug 18:30:153-166. doi: 10.1016/j.omto.2023.08.006. eCollection 2023 Sep 21.

Authors

Amos Hong Pheng Loh^{1

2

3}, Min Thura⁴, Abhishek Gupta⁴, Sheng Hui Tan¹, Kelvin Kam Yew Kuan⁴, Koon Hwee Ang⁴, Khurshid Merchant^{1

2

5}, Kenneth Tou En Chang^{1

2

5}, Hui Yi Yon⁵, Yong Chen^{2

3}, Mathew Hern Wang Cheng⁶, Arjandas Mahadev^{2

6}, Matthew Chau Hsien Ng^{2

7}, Michaela Su-Fern Seng^{1

2

8}, Prasad Iyer^{1

2

8}, Pei Ling Chia⁴, Shui Yen Soh^{1

2

8}, Qi Zeng^{4

9}

Affiliations

¹ VIVA-KKH Paediatric Brain and Solid Tumour Programme, Children's Blood and Cancer Centre, KK Women's and Children's Hospital Singapore 229899, Singapore.
² Duke-NUS School of Medicine, Singapore 169857, Singapore.
³ Department of Paediatric Surgery, KK Women's and Children's Hospital, Singapore 229899, Singapore.
⁴ Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology, and Research (A∗STAR), Singapore 138673, Singapore.
⁵ Department of Pathology and Laboratory Medicine, KK Women's and Children's Hospital, Singapore 229899, Singapore.
⁶ Department of Orthopaedic Surgery, KK Women's and Children's Hospital, Singapore 229899, Singapore.
⁷ Department of GI Oncology, National Cancer Centre Singapore, Singapore 229899, Singapore.
⁸ Department of Paediatric Subspecialties Haematology/Oncology Service, KK Women's and Children's Hospital, Singapore 229899, Singapore.
⁹ Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119260, Singapore.

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.

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