Identification of GPC2 as an Oncoprotein and Candidate Immunotherapeutic Target in High-Risk Neuroblastoma

Kristopher R Bosse; Pichai Raman; Zhongyu Zhu; Maria Lane; Daniel Martinez; Sabine Heitzeneder; Komal S Rathi; Nathan M Kendsersky; Michael Randall; Laura Donovan; Sorana Morrissy; Robyn T Sussman; Doncho V Zhelev; Yang Feng; Yanping Wang; Jennifer Hwang; Gonzalo Lopez; Jo Lynne Harenza; Jun S Wei; Bruce Pawel; Tricia Bhatti; Mariarita Santi; Arupa Ganguly; Javed Khan; Marco A Marra; Michael D Taylor; Dimiter S Dimitrov; Crystal L Mackall; John M Maris

doi:10.1016/j.ccell.2017.08.003

Identification of GPC2 as an Oncoprotein and Candidate Immunotherapeutic Target in High-Risk Neuroblastoma

Cancer Cell. 2017 Sep 11;32(3):295-309.e12. doi: 10.1016/j.ccell.2017.08.003.

Authors

Kristopher R Bosse¹, Pichai Raman², Zhongyu Zhu³, Maria Lane⁴, Daniel Martinez⁵, Sabine Heitzeneder⁶, Komal S Rathi², Nathan M Kendsersky⁴, Michael Randall⁴, Laura Donovan⁷, Sorana Morrissy⁷, Robyn T Sussman⁴, Doncho V Zhelev³, Yang Feng³, Yanping Wang³, Jennifer Hwang³, Gonzalo Lopez⁴, Jo Lynne Harenza⁴, Jun S Wei⁸, Bruce Pawel⁵, Tricia Bhatti⁵, Mariarita Santi⁵, Arupa Ganguly⁹, Javed Khan⁸, Marco A Marra¹⁰, Michael D Taylor⁷, Dimiter S Dimitrov³, Crystal L Mackall¹¹, John M Maris¹²

Affiliations

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 Neurosurgery and the Arthur and Sonia Labatt Brain Tumor Research Center, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
⁸ Oncogenomics Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
⁹ Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
¹⁰ 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.
¹¹ Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA.
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; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: maris@chop.edu.

Abstract

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.

Keywords: MYCN; antibody-drug conjugate; glypican; immunotherapy; medulloblastoma; neuroblastoma.

Publication types

Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Antibodies, Neoplasm / metabolism
Cell Death
Cell Line, Tumor
Cell Membrane / metabolism
Cell Proliferation
Child
Gene Expression Regulation, Neoplastic
Genome, Human
Glypicans / metabolism*
Humans
Immunotherapy*
Mice, Inbred NOD
Mice, SCID
Molecular Targeted Therapy*
N-Myc Proto-Oncogene Protein / metabolism
Neuroblastoma / genetics
Neuroblastoma / immunology*
Neuroblastoma / pathology
Neuroblastoma / therapy*
Oncogene Proteins / metabolism*
RNA, Messenger / genetics
RNA, Messenger / metabolism
Risk Factors

Substances

Antibodies, Neoplasm
GPC2 protein, human
Glypicans
MYCN protein, human
N-Myc Proto-Oncogene Protein
Oncogene Proteins
RNA, Messenger

Abstract

Publication types

MeSH terms

Substances

Grants and funding