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Tytuł pozycji:

Preclinical rationale for entinostat in embryonal rhabdomyosarcoma.

Tytuł:
Preclinical rationale for entinostat in embryonal rhabdomyosarcoma.
Autorzy:
Bharathy N; Children's Cancer Therapy Development Institute, 12655 Sw Beaverdam Rd. W, Beaverton, OR, 97005, USA. .
Berlow NE; Children's Cancer Therapy Development Institute, 12655 Sw Beaverdam Rd. W, Beaverton, OR, 97005, USA.
Wang E; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 11724, USA.
Abraham J; Department of Pediatrics, Oregon Health & Science University, Portland, OR, 97239, USA.
Settelmeyer TP; Children's Cancer Therapy Development Institute, 12655 Sw Beaverdam Rd. W, Beaverton, OR, 97005, USA.
Hooper JE; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
Svalina MN; Children's Cancer Therapy Development Institute, 12655 Sw Beaverdam Rd. W, Beaverton, OR, 97005, USA.
Bajwa Z; Children's Cancer Therapy Development Institute, 12655 Sw Beaverdam Rd. W, Beaverton, OR, 97005, USA.; Department of Pathology, Oregon Health & Science University, Portland, OR, 97239, USA.
Goros MW; Department of Epidemiology and Biostatistics, University of Texas Health Science Center, San Antonio, TX, 78229, USA.
Hernandez BS; Department of Epidemiology and Biostatistics, University of Texas Health Science Center, San Antonio, TX, 78229, USA.
Wolff JE; Department of Pediatric Hematology Oncology and Blood and Marrow Transplantation, Cleveland Clinic Children's, Cleveland, OH, 44195, USA.; Present Address: AbbVie, North Chicago, IL, 60064, USA.
Pal R; Electrical and Computer Engineering, Texas Tech University, Lubbock, TX, 79409, USA.
Davies AM; Champions Oncology, Rockville, MD, 20850, USA.
Ashok A; Champions Oncology, Rockville, MD, 20850, USA.
Bushby D; Champions Oncology, Rockville, MD, 20850, USA.
Mancini M; Champions Oncology, Rockville, MD, 20850, USA.
Noakes C; Champions Oncology, Rockville, MD, 20850, USA.
Goodwin NC; Champions Oncology, Rockville, MD, 20850, USA.
Ordentlich P; Syndax Pharmaceuticals, Waltham, MA, 02451, USA.
Keck J; The Jackson Laboratory, Sacramento, CA, 95838, USA.
Hawkins DS; Seattle Children's Hospital, Seattle, WA, 98105, USA.
Rudzinski ER; Seattle Children's Hospital, Seattle, WA, 98105, USA.
Mansoor A; Department of Pathology, Oregon Health & Science University, Portland, OR, 97239, USA.
Perkins TJ; Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, K1H 8L6, Canada.; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, K1H 8M5, Canada.
Vakoc CR; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 11724, USA.
Michalek JE; Department of Epidemiology and Biostatistics, University of Texas Health Science Center, San Antonio, TX, 78229, USA.
Keller C; Children's Cancer Therapy Development Institute, 12655 Sw Beaverdam Rd. W, Beaverton, OR, 97005, USA. .
Źródło:
Skeletal muscle [Skelet Muscle] 2019 May 21; Vol. 9 (1), pp. 12. Date of Electronic Publication: 2019 May 21.
Typ publikacji:
Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
Język:
English
Imprint Name(s):
Original Publication: [London] : BioMed Central Ltd., 2011-
MeSH Terms:
Benzamides/*therapeutic use
Histone Deacetylase Inhibitors/*therapeutic use
Pyridines/*therapeutic use
Rhabdomyosarcoma, Embryonal/*drug therapy
Adolescent ; Animals ; Antineoplastic Agents, Phytogenic/administration & dosage ; Antineoplastic Combined Chemotherapy Protocols/administration & dosage ; Benzamides/administration & dosage ; CRISPR-Cas Systems ; Cell Differentiation/drug effects ; Cell Line, Tumor ; Cellular Reprogramming/drug effects ; Cellular Reprogramming/genetics ; Child ; Child, Preschool ; Drug Screening Assays, Antitumor ; Female ; Histone Deacetylase 1/antagonists & inhibitors ; Histone Deacetylase 1/genetics ; Histone Deacetylase Inhibitors/administration & dosage ; Humans ; Male ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Pyridines/administration & dosage ; RNA-Seq ; Rhabdomyosarcoma, Alveolar/drug therapy ; Rhabdomyosarcoma, Alveolar/enzymology ; Rhabdomyosarcoma, Alveolar/pathology ; Rhabdomyosarcoma, Embryonal/enzymology ; Rhabdomyosarcoma, Embryonal/pathology ; Tumor Burden/drug effects ; Tumor Microenvironment/drug effects ; Tumor Microenvironment/genetics ; Vincristine/administration & dosage ; Xenograft Model Antitumor Assays
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Grant Information:
P30 CA045508 United States CA NCI NIH HHS; R01 CA143082 United States CA NCI NIH HHS; R01 CA189299 United States CA NCI NIH HHS
Contributed Indexing:
Keywords: Embryonal rhabdomyosarcoma (eRMS); Entinostat; HDAC3; Patient-derived xenograft (PDX); Vincristine
Substance Nomenclature:
0 (Antineoplastic Agents, Phytogenic)
0 (Benzamides)
0 (Histone Deacetylase Inhibitors)
0 (Pyridines)
1ZNY4FKK9H (entinostat)
5J49Q6B70F (Vincristine)
EC 3.5.1.98 (HDAC1 protein, human)
EC 3.5.1.98 (Hdac1 protein, mouse)
EC 3.5.1.98 (Histone Deacetylase 1)
Entry Date(s):
Date Created: 20190523 Date Completed: 20200504 Latest Revision: 20200522
Update Code:
20240104
PubMed Central ID:
PMC6528217
DOI:
10.1186/s13395-019-0198-x
PMID:
31113472
Czasopismo naukowe
Background: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in the pediatric cancer population. Survival among metastatic RMS patients has remained dismal yet unimproved for years. We previously identified the class I-specific histone deacetylase inhibitor, entinostat (ENT), as a pharmacological agent that transcriptionally suppresses the PAX3:FOXO1 tumor-initiating fusion gene found in alveolar rhabdomyosarcoma (aRMS), and we further investigated the mechanism by which ENT suppresses PAX3:FOXO1 oncogene and demonstrated the preclinical efficacy of ENT in RMS orthotopic allograft and patient-derived xenograft (PDX) models. In this study, we investigated whether ENT also has antitumor activity in fusion-negative eRMS orthotopic allografts and PDX models either as a single agent or in combination with vincristine (VCR).
Methods: We tested the efficacy of ENT and VCR as single agents and in combination in orthotopic allograft and PDX mouse models of eRMS. We then performed CRISPR screening to identify which HDAC among the class I HDACs is responsible for tumor growth inhibition in eRMS. To analyze whether ENT treatment as a single agent or in combination with VCR induces myogenic differentiation, we performed hematoxylin and eosin (H&E) staining in tumors.
Results: ENT in combination with the chemotherapy VCR has synergistic antitumor activity in a subset of fusion-negative eRMS in orthotopic "allografts," although PDX mouse models were too hypersensitive to the VCR dose used to detect synergy. Mechanistic studies involving CRISPR suggest that HDAC3 inhibition is the primary mechanism of cell-autonomous cytoreduction in eRMS. Following cytoreduction in vivo, residual tumor cells in the allograft models treated with chemotherapy undergo a dramatic, entinostat-induced (70-100%) conversion to non-proliferative rhabdomyoblasts.
Conclusion: Our results suggest that the targeting class I HDACs may provide a therapeutic benefit for selected patients with eRMS. ENT's preclinical in vivo efficacy makes ENT a rational drug candidate in a phase II clinical trial for eRMS.
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