ArticleNeuro-oncology2021
Heterogeneous delivery across the blood-brain barrier limits the efficacy of an EGFR-targeting antibody drug conjugate in glioblastoma.
Article in Neuro-oncology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 56 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
56 citing papers in PubMed, 1 synthesis or guideline pooled it, 77 citations in OpenAlex.
- Receptor tyrosine kinase targeted therapies in glioblastoma: a systematic review.Frontiers in medicine · 2026Pooled it
- Depatuxizumab mafodotin in EGFR-amplified newly diagnosed glioblastoma: A phase III randomized clinical trial.Neuro-oncology · 2023Trial
- EGFR-targeted antibody-toxin conjugate in recurrent glioma: a phase 1 trial.Nature medicine · 2026Article
- Article
- Uncovering the signaling networks of disseminated glioblastoma cells in vivo with INSIGHT.Nature communications · 2026Article
- Drug and single-cell gene expression integration identifies sensitive and resistant glioblastoma cell populations.Nature communications · 2026Article
- Targeting the C3 signaling axis of the complement system: immune microenvironment regulation and emerging therapeutic strategies for glioblastoma.Frontiers in immunology · 2026Review
- Nanobody-Based Drug Delivery: Emerging Strategies for Targeted Cancer Therapy.International journal of nanomedicine · 2026Review
- Drug resistance in glioblastoma: Challenges, mechanisms and therapeutic strategies (Review).Molecular and clinical oncology · 2026Review
- Development of an Active Chimeric IL13Rα2 ADC for Diffuse Intrinsic Pontine Glioma.ImmunoTargets and therapy · 2026Article
- Antibody-conjugated polymer nanoparticles for brain cancer.Drug delivery and translational research · 2025Review
- A surgical window of opportunity trial evaluating the effect of the PCSK9 inhibitor evolocumab on tumoral MHC-I expression and CD8Scientific reports · 2025Article
- Glioblastoma resistance to EGFR antibody-drug conjugate is driven by transcriptional reprogramming and TEK-induced EGFR suppression.Journal of translational medicine · 2025Article
- Current evidence and challenges of multitarget anti-angiogenic agents for glioblastoma: Results from clinical trials.iScience · 2025Review
- The impact of therapeutic radiation on drug distribution across the blood-brain barrier in normal mouse brain and orthotopic glioblastoma tumors.Neuro-oncology · 2025Article
- Hypoxia Imaging as a Radiomics Signature in Tumors Using NovelbioRxiv : the preprint server for biology · 2025Article
- Identification of Variable Lymphocyte Receptors That Target the Human Blood-Brain Barrier.Pharmaceutics · 2025Article
- Preclinical Modeling of Navtemadlin Pharmacokinetics, Pharmacodynamics, and Efficacy in IDH-Wild-type Glioblastoma.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Article
- Beyond the Walls of Troy: A Scoping Review on Pharmacological Strategies to Enhance Drug Delivery Across the Blood-Brain Barrier and Blood-Tumor Barrier.International journal of molecular sciences · 2025Article
- Exploring the Role of ADCs in Brain Metastases and Primary Brain Tumors: Insight and Future Directions.Cancers · 2025Review
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Authors and funding
30 authors at 6 institutions in 1 country.
Funding
Abstract
backgroundAntibody drug conjugates (ADCs) targeting the epidermal growth factor receptor (EGFR), such as depatuxizumab mafodotin (Depatux-M), is a promising therapeutic strategy for glioblastoma (GBM) but recent clinical trials did not demonstrate a survival benefit. Understanding the mechanisms of failure for this promising strategy is critically important.
methodsPDX models were employed to study efficacy of systemic vs intracranial delivery of Depatux-M. Immunofluorescence and MALDI-MSI were performed to detect drug levels in the brain. EGFR levels and compensatory pathways were studied using quantitative flow cytometry, Western blots, RNAseq, FISH, and phosphoproteomics.
resultsSystemic delivery of Depatux-M was highly effective in nine of 10 EGFR-amplified heterotopic PDXs with survival extending beyond one year in eight PDXs. Acquired resistance in two PDXs (GBM12 and GBM46) was driven by suppression of EGFR expression or emergence of a novel short-variant of EGFR lacking the epitope for the Depatux-M antibody. In contrast to the profound benefit observed in heterotopic tumors, only two of seven intrinsically sensitive PDXs were responsive to Depatux-M as intracranial tumors. Poor efficacy in orthotopic PDXs was associated with limited and heterogeneous distribution of Depatux-M into tumor tissues, and artificial disruption of the BBB or bypass of the BBB by direct intracranial injection of Depatux-M into orthotopic tumors markedly enhanced the efficacy of drug treatment.
conclusionsDespite profound intrinsic sensitivity to Depatux-M, limited drug delivery into brain tumor may have been a key contributor to lack of efficacy in recently failed clinical trials.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.