دورية أكاديمية
Tacedinaline (CI-994), a class I HDAC inhibitor, targets intrinsic tumor growth and leptomeningeal dissemination in MYC-driven medulloblastoma while making them susceptible to anti-CD47-induced macrophage phagocytosis via NF-kB-TGM2 driven tumor inflammation.
| العنوان: | Tacedinaline (CI-994), a class I HDAC inhibitor, targets intrinsic tumor growth and leptomeningeal dissemination in MYC-driven medulloblastoma while making them susceptible to anti-CD47-induced macrophage phagocytosis via NF-kB-TGM2 driven tumor inflammation. |
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| المؤلفون: | Marquardt V; Division of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany.; Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany., Theruvath J; Department of Neurosurgery, Institute for StemCell Biology and Regenerative Medicine and Division of Pediatric Neurosurgery, Lucile Packard Children's Hospital, Stanford University, Stanford, California, USA.; Stanford University School of Medicine, Stanford, California, USA., Pauck D; Division of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany.; Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany; and DKTK, partner site Essen/Düsseldorf, Germany, Düsseldorf, Germany., Picard D; Division of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany.; Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany; and DKTK, partner site Essen/Düsseldorf, Germany, Düsseldorf, Germany., Qin N; Division of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany.; Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany; and DKTK, partner site Essen/Düsseldorf, Germany, Düsseldorf, Germany., Blümel L; Division of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany.; Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany; and DKTK, partner site Essen/Düsseldorf, Germany, Düsseldorf, Germany., Maue M; Division of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany.; Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany; and DKTK, partner site Essen/Düsseldorf, Germany, Düsseldorf, Germany., Bartl J; Division of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany.; Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany; and DKTK, partner site Essen/Düsseldorf, Germany, Düsseldorf, Germany., Ahmadov U; Division of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany.; Institute of Neuropathology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf; and DKTK, partner site Essen/Düsseldorf, Germany, Düsseldorf, Germany., Langini M; Division of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany.; Molecular Proteomics Laboratory, Biomedical Research Centre (BMFZ), Heinrich-Heine University, Düsseldorf, Germany, Düsseldorf, Germany., Meyer FD; Division of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany.; Institute of Neuropathology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf; and DKTK, partner site Essen/Düsseldorf, Germany, Düsseldorf, Germany., Cole A; Pediatrics, University of Colorado Denver, Aurora, Colorado, USA., Cruz-Cruz J; Pediatrics, University of Colorado Denver, Aurora, Colorado, USA., Graef CM; Department of Neurosurgery, Institute for StemCell Biology and Regenerative Medicine and Division of Pediatric Neurosurgery, Lucile Packard Children's Hospital, Stanford University, Stanford, California, USA., Wölfl M; Department of Pediatric Oncology, University Children's Hospital Würzburg, Würzburg, Germany., Milde T; Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.; Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany., Witt O; Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.; Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany., Erdreich-Epstein A; Division of Hematology-Oncology and Blood and Marrow Transplantation, Department of Pediatrics and the Department of Pathology, Children's Hospital Los Angeles, and the Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, USA., Leprivier G; Institute of Neuropathology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf; and DKTK, partner site Essen/Düsseldorf, Germany, Düsseldorf, Germany., Kahlert U; Department of Neurosurgery, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany., Stefanski A; Molecular Proteomics Laboratory, Biomedical Research Centre (BMFZ), Heinrich-Heine University, Düsseldorf, Germany, Düsseldorf, Germany., Stühler K; Molecular Proteomics Laboratory, Biomedical Research Centre (BMFZ), Heinrich-Heine University, Düsseldorf, Germany, Düsseldorf, Germany., Keir ST; Department of Neurosurgery, Duke University, Durham, North Carolina, USA.; Preston Robert Tisch Brain Tumor Center, Duke University, Durham, North Carolina, USA., Bigner DD; Department of Neurosurgery, Duke University, Durham, North Carolina, USA.; Preston Robert Tisch Brain Tumor Center, Duke University, Durham, North Carolina, USA., Hauer J; Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany; and DKTK, partner site Essen/Düsseldorf, Germany, Düsseldorf, Germany., Beez T; Department of Neurosurgery, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany., Knobbe-Thomsen CB; Institute of Neuropathology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf; and DKTK, partner site Essen/Düsseldorf, Germany, Düsseldorf, Germany., Fischer U; Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany; and DKTK, partner site Essen/Düsseldorf, Germany, Düsseldorf, Germany., Felsberg J; Institute of Neuropathology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf; and DKTK, partner site Essen/Düsseldorf, Germany, Düsseldorf, Germany., Hansen FK; Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.; Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Leipzig University, Leipzig, Germany., Vibhakar R; Pediatrics, University of Colorado Denver, Aurora, Colorado, USA., Venkatraman S; Pediatrics, University of Colorado Denver, Aurora, Colorado, USA., Cheshier SH; Department of Neurosurgery, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA., Reifenberger G; Division of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany.; Institute of Neuropathology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf; and DKTK, partner site Essen/Düsseldorf, Germany, Düsseldorf, Germany., Borkhardt A; Division of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany.; Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany., Kurz T; Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany., Remke M; Division of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany siddhartha.mitra@cuanschutz.edu Marc.Remke@med.uni-duesseldorf.de.; Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany; and DKTK, partner site Essen/Düsseldorf, Germany, Düsseldorf, Germany., Mitra S; Pediatrics, University of Colorado Denver, Aurora, Colorado, USA siddhartha.mitra@cuanschutz.edu Marc.Remke@med.uni-duesseldorf.de. |
| المصدر: | Journal for immunotherapy of cancer [J Immunother Cancer] 2023 Jan; Vol. 11 (1). |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: BMJ Publishing Group Ltd Country of Publication: England NLM ID: 101620585 Publication Model: Print Cited Medium: Internet ISSN: 2051-1426 (Electronic) Linking ISSN: 20511426 NLM ISO Abbreviation: J Immunother Cancer Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2020- : London, United Kingdom : BMJ Publishing Group Ltd. Original Publication: London : BioMed Central, 2013- |
| مواضيع طبية MeSH: | Medulloblastoma*/drug therapy , Glioblastoma* , Cerebellar Neoplasms*, Humans ; Mice ; Animals ; NF-kappa B/metabolism ; Histone Deacetylase Inhibitors/pharmacology ; Histone Deacetylase Inhibitors/therapeutic use ; Protein Glutamine gamma Glutamyltransferase 2 ; Quality of Life ; Phagocytosis ; Macrophages ; Inflammation/metabolism |
| مستخلص: | Background: While major advances have been made in improving the quality of life and survival of children with most forms of medulloblastoma (MB), those with MYC-driven tumors (Grp3-MB) still suffer significant morbidity and mortality. There is an urgent need to explore multimodal therapeutic regimens which are effective and safe for children. Large-scale studies have revealed abnormal cancer epigenomes caused by mutations and structural alterations of chromatin modifiers, aberrant DNA methylation, and histone modification signatures. Therefore, targeting epigenetic modifiers for cancer treatment has gained increasing interest, and inhibitors for various epigenetic modulators have been intensively studied in clinical trials. Here, we report a cross-entity, epigenetic drug screen to evaluate therapeutic vulnerabilities in MYC amplified MB, which sensitizes them to macrophage-mediated phagocytosis by targeting the CD47-signal regulatory protein α (SIRPα) innate checkpoint pathway. Methods: We performed a primary screen including 78 epigenetic inhibitors and a secondary screen including 20 histone deacetylase inhibitors (HDACi) to compare response profiles in atypical teratoid/rhabdoid tumor (AT/RT, n=11), MB (n=14), and glioblastoma (n=14). This unbiased approach revealed the preferential activity of HDACi in MYC-driven MB. Importantly, the class I selective HDACi, CI-994, showed significant cell viability reduction mediated by induction of apoptosis in MYC-driven MB, with little-to-no activity in non-MYC-driven MB, AT/RT, and glioblastoma in vitro. We tested the combinatorial effect of targeting class I HDACs and the CD47-SIRPa phagocytosis checkpoint pathway using in vitro phagocytosis assays and in vivo orthotopic xenograft models. Results: CI-994 displayed antitumoral effects at the primary site and the metastatic compartment in two orthotopic mouse models of MYC-driven MB. Furthermore, RNA sequencing revealed nuclear factor-kB (NF-κB) pathway induction as a response to CI-994 treatment, followed by transglutaminase 2 (TGM2) expression, which enhanced inflammatory cytokine secretion. We further show interferon-γ release and cell surface expression of engulfment ('eat-me') signals (such as calreticulin). Finally, combining CI-994 treatment with an anti-CD47 mAb targeting the CD47-SIRPα phagocytosis checkpoint enhanced in vitro phagocytosis and survival in tumor-bearing mice. Conclusion: Together, these findings suggest a dynamic relationship between MYC amplification and innate immune suppression in MYC amplified MB and support further investigation of phagocytosis modulation as a strategy to enhance cancer immunotherapy responses. Competing Interests: Competing interests: SHC and SSM hold a Patent entitled ‘Treatment of pediatric brain tumors with targeting of CD47 pathway’. Other authors hold no potential conflict of interest. (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.) |
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| معلومات مُعتمدة: | P30 CA014236 United States CA NCI NIH HHS; P30 CA046934 United States CA NCI NIH HHS; S10 OD023485 United States OD NIH HHS; S10 OD027023 United States OD NIH HHS |
| فهرسة مساهمة: | Keywords: Brain Neoplasms; Cytotoxicity, Immunologic; Immunotherapy; Macrophages; Phagocytosis |
| المشرفين على المادة: | UMF554N5FG (tacedinaline) 0 (NF-kappa B) 0 (Histone Deacetylase Inhibitors) EC 2.3.2.13 (Protein Glutamine gamma Glutamyltransferase 2) |
| تواريخ الأحداث: | Date Created: 20230113 Date Completed: 20230117 Latest Revision: 20230404 |
| رمز التحديث: | 20230404 |
| مُعرف محوري في PubMed: | PMC9843227 |
| DOI: | 10.1136/jitc-2022-005871 |
| PMID: | 36639156 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 2051-1426 |
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| DOI: | 10.1136/jitc-2022-005871 |