Using a multimodal approach Bosse et al. identified the differentially expressed cell-surface oncoprotein GPC2 as an optimal immunotherapeutic target in neuroblastoma (NB) and other pediatric embryonal malignancies. While GPC2 was found to be critical for NB proliferation, its expression in normal cells was limited. Bosse et al. further developed an antibody-drug conjugate that is efficacious against GPC2-expressing cells in vitro and in a NB patient-derived xenograft model.
We developed an RNA-sequencing-based pipeline to discover differentially expressed cell-surface molecules in neuroblastoma that meet criteria for optimal immunotherapeutic target safety and efficacy. Here, we show that GPC2 is a strong candidate immunotherapeutic target in this childhood cancer. We demonstrate high GPC2 expression in neuroblastoma due to MYCN transcriptional activation and/or somatic gain of the GPC2 locus. We confirm GPC2 to be highly expressed on most neuroblastomas, but not detectable at appreciable levels in normal childhood tissues. In addition, we demonstrate that GPC2 is required for neuroblastoma proliferation. Finally, we develop a GPC2-directed antibody-drug conjugate that is potently cytotoxic to GPC2-expressing neuroblastoma cells. Collectively, these findings validate GPC2 as a non-mutated neuroblastoma oncoprotein and candidate immunotherapeutic target.
Author Info: (1) Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Colket Translational Research Building, 3501 Civic Center Boulevard, Philade
Author Info: (1) Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Colket Translational Research Building, 3501 Civic Center Boulevard, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (2) Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Colket Translational Research Building, 3501 Civic Center Boulevard, Philadelphia, PA 19104, USA; Department of Biomedical and Health Informatics and Center for Data-Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. (3) Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21701, USA. (4) Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Colket Translational Research Building, 3501 Civic Center Boulevard, Philadelphia, PA 19104, USA. (5) Department of Pathology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. (6) Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA. (7) Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Colket Translational Research Building, 3501 Civic Center Boulevard, Philadelphia, PA 19104, USA; Department of Biomedical and Health Informatics and Center for Data-Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. (8) Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Colket Translational Research Building, 3501 Civic Center Boulevard, Philadelphia, PA 19104, USA. (9) Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Colket Translational Research Building, 3501 Civic Center Boulevard, Philadelphia, PA 19104, USA. (10) Division of Neurosurgery and the Arthur and Sonia Labatt Brain Tumor Research Center, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada. (11) Division of Neurosurgery and the Arthur and Sonia Labatt Brain Tumor Research Center, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada. (12) Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Colket Translational Research Building, 3501 Civic Center Boulevard, Philadelphia, PA 19104, USA. (13) Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21701, USA. (14) Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21701, USA. (15) Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21701, USA. (16) Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21701, USA. (17) Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Colket Translational Research Building, 3501 Civic Center Boulevard, Philadelphia, PA 19104, USA. (18) Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Colket Translational Research Building, 3501 Civic Center Boulevard, Philadelphia, PA 19104, USA. (19) Oncogenomics Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. (20) Department of Pathology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. (21) Department of Pathology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. (22) Department of Pathology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. (23) Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (24) Oncogenomics Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. (25) Genome Sciences Center, British Columbia Cancer Agency, University of British Columbia, Vancouver, BC V6T 1Z4, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z4, Canada. (26) Division of Neurosurgery and the Arthur and Sonia Labatt Brain Tumor Research Center, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada. (27) Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21701, USA. (28) Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA. (29) Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Colket Translational Research Building, 3501 Civic Center Boulevard, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: maris@chop.edu.
