ArticleCancer cell2024
A proteogenomic surfaceome study identifies DLK1 as an immunotherapeutic target in neuroblastoma.
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Article in Cancer cell, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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18 citing papers in PubMed.
- Chimeric antigen receptor (CAR)-T cell therapy for solid tumors in pediatric patients: current breakthroughs, dilemmas, and strategies.Experimental hematology & oncology · 2026Review
- Single-cell transcriptomic atlas-guided NRG3-ERBB4 axis enhances the efficacy of chemo-immunotherapy during induction phase in high-risk neuroblastoma.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Article
- DLK1 is a GATA1s-driven dependency and therapeutic target in Down syndrome-associated myeloid leukemia.Blood advances · 2026Article
- DLK1: a novel therapeutic target in cancer.Endocrine-related cancer · 2026Review
- Epigenetic Regulation of Trk Receptors and Neurotrophic Signalling in Neuroblastoma: Mechanisms, Plasticity, and Therapeutic Opportunities.International journal of molecular sciences · 2026Review
- Advances in multi-omics research on neuroblastoma.Frontiers in pediatrics · 2026Review
- Postnatal sustentacular cells as chromaffin progenitors and tumor cells of origin in VHL-related paragangliomas.NPJ precision oncology · 2025Article
- NRCAM variant defined by microexon skipping is a targetable cell surface proteoform in high-grade gliomas.Cell reports · 2025Article
- A humanized anaplastic lymphoma kinase (ALK)-directed antibody-drug conjugate with pyrrolobenzodiazepine payload demonstrates efficacy in ALK-expressing cancers.Nature communications · 2025Article
- Identification of Crucial Genes Associated With MYCN-Driven Neuroblastoma Based on Single-Cell Analysis and Machine Learning.Cancer medicine · 2025Article
- Identification of the Notch ligand DLK1 as an immunotherapeutic target and regulator of tumor cell plasticity and chemoresistance in adrenocortical carcinoma.Nature communications · 2025Article
- Evaluation of DNA Methylation and Expression of DLK1 and MEG3 Genes in Placenta and Umbilical Cord Blood Samples of Infertile People after ICSI-AOA Method.Reproductive sciences (Thousand Oaks, Calif.) · 2025Article
- Comparative Single-Cell Transcriptomics of Human Neuroblastoma and Preclinical Models Reveals Conservation of an Adrenergic Cell State.Cancer research · 2025Article
- ImmunoTar-integrative prioritization of cell surface targets for cancer immunotherapy.Bioinformatics (Oxford, England) · 2025Article
- Epidemiological characteristics and disease burden of childhood neuroblastoma in Asia: trends and regional differences over the past 30 years.Frontiers in pediatrics · 2025Article
- Emerging clinical and research approaches in targeted therapies for high-risk neuroblastoma.Frontiers in oncology · 2025Review
- Lessons learned from 20 years of preclinical testing in pediatric cancers.Pharmacology & therapeutics · 2024Review
- IMMUNOTAR - Integrative prioritization of cell surface targets for cancer immunotherapy.bioRxiv : the preprint server for biology · 2024Article
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Authors and funding
38 authors.
Amber K HamiltonCenter for Childhood Cancer Research and Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Alexander B RadaouiCenter for Childhood Cancer Research and Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Matthew TsangCenter for Childhood Cancer Research and Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Daniel MartinezDepartment of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Karina L ConkriteCenter for Childhood Cancer Research and Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Khushbu PatelCenter for Childhood Cancer Research and Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Simone SidoliDepartment of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Alberto DelaidelliDepartment of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada; Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada.
Apexa ModiCenter for Childhood Cancer Research and Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Jo Lynne RokitaCenter for Data-Driven Discovery in Biomedicine and Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Maria V LaneCenter for Childhood Cancer Research and Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Nicholas HartnettCenter for Childhood Cancer Research and Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Raphael D LopezCenter for Childhood Cancer Research and Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Bo ZhangCenter for Data-Driven Discovery in Biomedicine and Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Chuwei ZhongCenter for Data-Driven Discovery in Biomedicine and Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Brian EnnisCenter for Data-Driven Discovery in Biomedicine and Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Daniel P MillerCenter for Data-Driven Discovery in Biomedicine and Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Miguel A BrownCenter for Data-Driven Discovery in Biomedicine and Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Komal S RathiCenter 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.
Pichai RamanCenter 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.
Jennifer PogorilerDepartment of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Tricia BhattiDepartment of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Bruce PawelDepartment of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Tina Glisovic-AplencCenter for Childhood Cancer Research and Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Beverly TeicherNational Cancer Institute, Bethesda, MD 20892, USA.
Stephen W EricksonRTI International, Research Triangle Park, Durham, NC 27709, USA.
Eric J EarleyRTI International, Research Triangle Park, Durham, NC 27709, USA.
Kristopher R BosseCenter 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.
Poul H SorensenDepartment of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada; Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada.
Kateryna KrytskaCenter for Childhood Cancer Research and Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Yael P MosseCenter 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.
Karin E HavenithADC Therapeutics (UK) Ltd, London W12 0BZ, UK.
Francesca ZammarchiADC Therapeutics (UK) Ltd, London W12 0BZ, UK.
Patrick H van BerkelADC Therapeutics (UK) Ltd, London W12 0BZ, UK.
Malcolm A SmithNational Cancer Institute, Bethesda, MD 20892, USA.
Benjamin A GarciaDepartment of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
John M MarisCenter 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. Electronic address: maris@chop.edu.
Sharon J DiskinCenter 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. Electronic address: diskin@chop.edu.
Funding
IMMUNOBIOLOGY OF NORMAL AND NEOPLASTIC LYMPHOCYTEST32CA009140 · NCI · UNIVERSITY OF PENNSYLVANIA · PI Malay Haldar, WARREN S PEAR · 1985 to 2026
$16.1MUnderstanding and Overcoming Resistance to Immunotherapies in Childhood CancersU54CA232568 · NCI · CHILDREN'S HOSP OF PHILADELPHIA · PI MACKALL, CRYSTAL, MARIS, JOHN M · 2018 to 2022
$13.1MDiscovering mechanisms of neuroblastoma tumorigenesis to improve patient outcomesR35CA220500 · NCI · CHILDREN'S HOSP OF PHILADELPHIA · PI JOHN M MARIS · 2017 to 2026
$8.7MNCI Pediatric In Vivo Testing Program: NeuroblastomaU01CA263957 · NCI · CHILDREN'S HOSP OF PHILADELPHIA · PI MOSSE, YAEL P · 2021 to 2025
$3.5MNextGen - CHOPOT2CA278687 · NCI · CHILDREN'S HOSP OF PHILADELPHIA · PI JOHN M MARIS · 2022 to 2026
$2.7MPediatric Preclinical Testing Consortium: Coordinating Center-Additional PPTC funding extensionU01CA199222 · NCI · RESEARCH TRIANGLE INSTITUTE · PI GATTO, GREGORY J · 2015 to 2021
$2.6MPediatric Preclinical Testing ConsortiumU01CA199287 · NCI · CHILDREN'S HOSP OF PHILADELPHIA · PI MARIS, JOHN M · 2015 to 2021
$2.1MElucidating the role of the noncoding genome in neuroblastomaR01CA237562 · NCI · CHILDREN'S HOSP OF PHILADELPHIA · PI DISKIN, SHARON · 2021 to 2025
$2.0MStructural Variation in NeuroblastomaR01CA204974 · NCI · CHILDREN'S HOSP OF PHILADELPHIA · PI DISKIN, SHARON · 2016 to 2020
$1.9MGPC2 CARs in neuroblastoma: Mechanisms of resistance and efficacy of next-generation constructsR37CA282041 · NCI · CHILDREN'S HOSP OF PHILADELPHIA · PI Kristopher R Bosse · 2024 to 2026
$1.8MDiscovering the genetic basis of neuroblastoma initiation and progressionR03CA230366 · NCI · CHILDREN'S HOSP OF PHILADELPHIA · PI DISKIN, SHARON · 2018 to 2019
$344kAn integrative approach to identify neuroblastoma immunotherapeutic targetsF31CA225069 · NCI · UNIVERSITY OF PENNSYLVANIA · PI HAMILTON, AMBER · 2018 to 2020
$104kCancer Research UK CGCATF-2021/100014NCI NIH HHS F31 CA225069NCI NIH HHS OT2 CA278687NCI NIH HHS R01 CA204974NCI NIH HHS R01 CA237562NCI NIH HHS R03 CA230366NCI NIH HHS R35 CA220500NCI NIH HHS R37 CA282041NCI NIH HHS T32 CA009140NCI NIH HHS U01 CA199222NCI NIH HHS U01 CA199287NCI NIH HHS U01 CA263957NCI NIH HHS U54 CA232568
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.
Indexed as
Antineoplastic Agents, ImmunologicalCalcium-Binding ProteinsImmunoconjugatesMembrane ProteinsNeuroblastomaAnimalsBiomarkers, TumorCell Line, TumorChildFemaleGene Expression Regulation, NeoplasticHumansImmunotherapyKaplan-Meier EstimateMiceMice, SCIDAntineoplastic Agents, ImmunologicalBiomarkers, TumorCalcium-Binding ProteinsDLK1 protein, humanImmunoconjugatesMembrane Proteinsantibody-drug conjugatecancerDLK1immunotherapymass spectrometryneuroblastomasurfaceome
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