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Journal Article Ppublish 4 citations

PubMed: 39454577 DOI: 10.1016/j.ccell.2024.10.003

A proteogenomic surfaceome study identifies DLK1 as an immunotherapeutic target in neuroblastoma.

Cancer Cell 42(11):1970-1982.e7

Authors: Amber K Hamilton, Alexander B Radaoui, Matthew Tsang, Daniel Martinez, Karina L Conkrite, Khushbu Patel, Simone Sidoli, Alberto Delaidelli, Apexa Modi, Jo Lynne Rokita, Maria V Lane, Nicholas Hartnett, Raphael D Lopez, Bo Zhang, Chuwei Zhong, Brian Ennis, Daniel P Miller, Miguel A Brown, Komal S Rathi, Pichai Raman, Jennifer Pogoriler, Tricia Bhatti, Bruce Pawel, Tina Glisovic-Aplenc, Beverly Teicher, Stephen W Erickson, Eric J Earley, Kristopher R Bosse, Poul H Sorensen, Kateryna Krytska, Yael P Mosse, Karin E Havenith, Francesca Zammarchi, Patrick H van Berkel, Malcolm A Smith, Benjamin A Garcia, John M Maris, Sharon J Diskin

Affiliations

  • Center for Childhood Cancer Research and Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
  • Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada; Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada.
  • Center for Data-Driven Discovery in Biomedicine and Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • Center for Childhood Cancer Research and Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Center for Data-Driven Discovery in Biomedicine and Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • National Cancer Institute, Bethesda, MD 20892, USA.
  • RTI International, Research Triangle Park, Durham, NC 27709, USA.
  • Center for Childhood Cancer Research and Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • ADC Therapeutics (UK) Ltd, London W12 0BZ, UK.
  • Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Center for Childhood Cancer Research and Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Center for Childhood Cancer Research and Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Abstract

Cancer immunotherapies produce remarkable results in B cell malignancies; however, optimal cell surface targets for many solid cancers remain elusive. Here, we present an integrative proteomic, transcriptomic, and epigenomic analysis of tumor and normal tissues to identify biologically relevant cell surface immunotherapeutic targets for neuroblastoma, an often-fatal childhood cancer. Proteogenomic analyses reveal sixty high-confidence candidate immunotherapeutic targets, and we prioritize delta-like canonical notch ligand 1 (DLK1) for further study. High expression of DLK1 directly correlates with a super-enhancer. Immunofluorescence, flow cytometry, and immunohistochemistry show robust cell surface expression of DLK1. Short hairpin RNA mediated silencing of DLK1 in neuroblastoma cells results in increased cellular differentiation. ADCT-701, a DLK1-targeting antibody-drug conjugate (ADC), shows potent and specific cytotoxicity in DLK1-expressing neuroblastoma xenograft models. Since high DLK1 expression is found in several adult and pediatric cancers, our study demonstrates the utility of a proteogenomic approach and credentials DLK1 as an immunotherapeutic target.

MeSH

Cells, Neoplasms, Proteogenomics, Immunotherapy, Neuroblastoma

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