pyrimidinones and Histiocytic-Sarcoma

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Cell Transdifferentiation; Head and Neck Neoplasms; Histiocytic Sarcoma; Humans; Imidazoles; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Oximes; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones

Topics: Amino Acid Substitution; Histiocytic Sarcoma; Humans; Imidazoles; Infant; Male; Mutation, Missense; Neoplasms, Second Primary; Oximes; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Histiocytic sarcoma in advanced clinical stages is typically an aggressive neoplasm, with poor response to conventional chemotherapy. An 18-year-old male with refractory histiocytic sarcoma that had transformed from Rosai-Dorfman disease was admitted to our hospital. A pathogenic variant of MAP2K1 was detected by next-generation sequencing of tumor specimens. Affected regions showed excellent responses to the MEK inhibitor trametinib. It has been reported that RAS/MEK/ERK pathway is activated in many cases of histiocytic sarcoma. MEK inhibition may represent a useful treatment option in histiocytic sarcoma.

Topics: Adolescent; Histiocytic Sarcoma; Humans; Male; MAP Kinase Kinase 1; MAP Kinase Signaling System; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Recurrence; Treatment Outcome

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Biopsy; Combined Modality Therapy; Histiocytic Sarcoma; Humans; Imatinib Mesylate; Immunohistochemistry; Immunophenotyping; Male; Molecular Targeted Therapy; Positron Emission Tomography Computed Tomography; Pyridones; Pyrimidinones; Retreatment; Symptom Assessment; Treatment Outcome

Topics: Histiocytic Sarcoma; Humans; Imatinib Mesylate; Protein-Tyrosine Kinases; Pyridones; Pyrimidinones

Topics: Histiocytic Sarcoma; Humans; Male; MAP Kinase Kinase 1; Metabolic Networks and Pathways; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Mutation; Protein Kinase Inhibitors; Pyridones; Pyrimidinones

Histiocytic sarcoma in humans is an aggressive orphan disease with a poor prognosis as treatment options are limited. Dogs are the only species that spontaneously develops histiocytic sarcoma with an appreciable frequency, and may have value as a translational model system. In the current study, high-throughput drug screening utilizing histiocytic sarcoma cells isolated from canine neoplasms identified these cells as particularly sensitive to a MEK inhibitor, trametinib. One of the canine cell lines carries a mutation in PTPN11 (E76K), and another one in KRAS (Q61H), which are associated with the activation of oncogenic MAPK signaling. Both mutations were previously reported in human histiocytic sarcoma. Trametinib inhibited sensitive cell lines by promoting cell apoptosis, indicated by a significant increase in caspase 3/7. Furthermore,

Topics: Animals; Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Dogs; Down-Regulation; Female; Histiocytic Sarcoma; Liver; MAP Kinase Signaling System; Mice, Inbred NOD; Mice, SCID; Mitogen-Activated Protein Kinase Kinases; Models, Biological; Molecular Targeted Therapy; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Pyridones; Pyrimidinones; Survival Analysis; Translational Research, Biomedical; Up-Regulation; Xenograft Model Antitumor Assays