ArticleJournal of the National Cancer Institute2020
Hematopoietic Stem Cell Gene Therapy for Brain Metastases Using Myeloid Cell-Specific Gene Promoters.
Article in Journal of the National Cancer Institute, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 22 citations in OpenAlex.
- The Origin of Cancer-Associated Fibroblasts (CAFs) in Brain Metastases: Seven Hypotheses and Current Evidence.Cancers · 2026Review
- Are monocytes a preferable option to develop myeloid cell-based therapies for solid tumors?Journal of experimental & clinical cancer research : CR · 2025Review
- Predictive factors and outcomes of immune-related adverse events in Chinese patients treated with immune checkpoint inhibitors: a real-world retrospective study.Frontiers in immunology · 2025Article
- Micro/nanosystems for controllable drug delivery to the brain.Innovation (Cambridge (Mass.)) · 2024Review
- Pseudotyped lentiviral vectors: Ready for translation into targeted cancer gene therapy?Genes & diseases · 2023Review
- Lentiviral vectors for inducible, transactivator-free advanced therapy medicinal products: Application to CAR-T cells.Molecular therapy. Nucleic acids · 2023Article
- Stemness genes and miR-1247-3p expression associate with clinicopathological parameters and prognosis in lung adenocarcinoma.PloS one · 2023Article
- Biglycan and reduced glycolysis are associated with breast cancer cell dormancy in the brain.Frontiers in oncology · 2023Article
- Mapping molecular subtype specific alterations in breast cancer brain metastases identifies clinically relevant vulnerabilities.Nature communications · 2022Article
- Hematopoietic Stem Cell Transplantation for Neurological Disorders: A Focus on Inborn Errors of Metabolism.Frontiers in cellular neuroscience · 2022Review
- Aging and CNS Myeloid Cell Depletion Attenuate Breast Cancer Brain Metastasis.Clinical cancer research : an official journal of the American Association for Cancer Research · 2021Article
- Review
- Emerging principles of brain immunology and immune checkpoint blockade in brain metastases.Brain : a journal of neurology · 2021Review
- Strategies for delivering therapeutics across the blood-brain barrier.Nature reviews. Drug discovery · 2021Review
- Hematopoietic stem cell gene therapy targeting TGFβ enhances the efficacy of irradiation therapy in a preclinical glioblastoma model.Journal for immunotherapy of cancer · 2021Article
- Brain Metastasis Cell Lines Panel: A Public Resource of Organotropic Cell Lines.Cancer research · 2020Review
Corrections and comments
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Authors and funding
15 authors at 3 institutions in 2 countries.
Funding
Abstract
backgroundBrain metastases (BrM) develop in 20-40% of cancer patients and represent an unmet clinical need. Limited access of drugs into the brain because of the blood-brain barrier is at least partially responsible for therapeutic failure, necessitating improved drug delivery systems.
methodsGreen fluorescent protein (GFP)-transduced murine and nontransduced human hematopoietic stem cells (HSCs) were administered into mice (n = 10 and 3). The HSC progeny in mouse BrM and in patient-derived BrM tissue (n = 6) was characterized by flow cytometry and immunofluorescence. Promoters driving gene expression, specifically within the BrM-infiltrating HSC progeny, were identified through differential gene-expression analysis and subsequent validation of a series of promoter-green fluorescent protein-reporter constructs in mice (n = 5). One of the promoters was used to deliver tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to BrM in mice (n = 17/21 for TRAIL vs control group).
resultsHSC progeny (consisting mostly of macrophages) efficiently homed to macrometastases (mean [SD] = 37.6% [7.2%] of all infiltrating cells for murine HSC progeny; 27.9% mean [SD] = 27.9% [4.9%] of infiltrating CD45+ hematopoietic cells for human HSC progeny) and micrometastases in mice (19.3-53.3% of all macrophages for murine HSCs). Macrophages were also abundant in patient-derived BrM tissue (mean [SD] = 8.8% [7.8%]). Collectively, this provided a rationale to optimize the delivery of gene therapy to BrM within myeloid cells. MMP14 promoter emerged as the strongest promoter construct capable of limiting gene expression to BrM-infiltrating myeloid cells in mice. TRAIL delivered under MMP14 promoter statistically significantly prolonged survival in mice (mean [SD] = 19.0 [3.4] vs mean [SD] = 15.0 [2.0] days for TRAIL vs control group; two-sided P = .006), demonstrating therapeutic and translational potential of our approach.
conclusionsOur study establishes HSC gene therapy using a myeloid cell-specific promoter as a new strategy to target BrM. This approach, with strong translational value, has potential to overcome the blood-brain barrier, target micrometastases, and control multifocal lesions.
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