pyrimidinones and Meningeal-Neoplasms

Rhabdoid meningioma is an aggressive phenotype of meningioma, associated with a poor prognosis. We present a very rare case of high-grade meningioma with rhabdoid features that eventually expressed in a coma state. Comprehensive genomic profiling using a Next Generation Sequencing (NGS) assay revealed three genomic alterations: activating BRAF mutation (V600E), loss of CDKN2A/2B, and APC I1307K. After treatment with BRAF inhibitor (dabrafenib), the child's clinical condition improved progressively. After seven months, an MEK inhibitor was added (trametinib).

Topics: Adenomatous Polyposis Coli Protein; Antineoplastic Agents; Child; Cyclin-Dependent Kinase Inhibitor p15; Cyclin-Dependent Kinase Inhibitor p16; Female; Gene Expression Profiling; High-Throughput Nucleotide Sequencing; Humans; Imidazoles; Magnetic Resonance Imaging; Meningeal Neoplasms; Meningioma; Mutation; Oximes; Precision Medicine; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Rhabdoid Tumor

Congenital melanocytic nevus (CMN) syndrome represents a mosaic RASopathy, typically caused by postzygotic NRAS codon 61 mutations, which originate in ectodermal precursor cells and result in melanocyte deposits in the skin and central nervous system (CNS). Affected patients are prone to develop uniformly fatal melanomas in the skin and CNS. Here, we report the case of a 2.7-year-old male with CMN syndrome, diffuse leptomeningeal melanosis and CNS melanoma, who underwent experimental therapy with the DNA methyltransferase inhibitor azacitidine in combination with the mitogen-activated protein kinase (MEK) inhibitor trametinib with exceptional clinical and radiological response. Response to combination therapy appeared to be more durable than the treatment response observed in several other severely affected patients treated with trametinib for late-stage disease. Correspondingly, concomitant exposure to trametinib and azacitidine prevented development of trametinib resistance in NRAS-mutated human melanoma cells in vitro. Also, azacitidine was shown to inhibit growth and mitogen-activated protein kinase 1/2 (ERK1/2) phosphorylation of melanoma cells and act synergistically with trametinib to inhibit the growth of trametinib-resistant melanoma cells. These observations suggest that azacitidine enhances trametinib monotherapy and may represent a promising candidate drug for combination therapies to enhance the efficacy of MEK inhibitors in RAS-driven diseases.

Topics: Azacitidine; Child, Preschool; GTP Phosphohydrolases; Humans; Male; Melanoma; Membrane Proteins; Meningeal Neoplasms; Mitogen-Activated Protein Kinase Kinases; Mutation; Nevus, Pigmented; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Skin Neoplasms

Recent studies suggest that HIV-1 protease inhibitors may have anti-neoplastic effects on some malignancies. The anti-neoplastic effects of lopinavir have not been established or studied in brain tumors. Primary cultures of three fetal leptomeninges and 18 meningiomas were treated with lopinavir alone or with PDGF-BB. DNA synthesis was assessed by CyQUANT. Lopinavir effects on basal and PDGF-stimulated phosphorylation of the Akt-mTOR, MEK1/2-MAPK and STAT3 pathways, phosphorylation of Rb, Caspase 3 activation and reductions in survivin were assessed by Western blots. Lopinavir produced a significant reduction in PDGF-BB stimulation of DNA synthesis in a leptomeningeal culture (P = 0.0013) and 1 of 6 WHO grade I and 1 of 4 grade II meningiomas at 24 h and in 3 of 6 WHO grade I, 4 of 4 grade II and 1 of 1 grade III cell cultures (P = 0.0001) at 72 h. Lopinavir reduced PDGF-BB stimulation of phosphorylation/activation of MAPK in the 22 week fetal leptomeningeal cell cultures and in cells from 1 grade I meningioma at 24 h, but in none of 4 grade I and 5 grade II meningiomas at 6 h. Lopinavir had no notable effect on basal or PDGF-stimulated p-mTOR, p-MEK1/2, or p-STAT3, activation of Caspase 3 or survivin levels. Lopinavir treatment for 24 h had no effect on basal Rb phosphorylation but reduced Rb phosphorylation in all four meningioma cultures. These studies suggest that lopinavir may inhibit meningioma growth, and does so in part by cell cycle arrest. Additional evaluation of lopinavir as a potential adjunct chemotherapy is warranted.

Topics: Adult; Aged; Aged, 80 and over; Apoptosis; Becaplermin; Blotting, Western; Caspase 3; Cell Proliferation; Female; HIV Protease Inhibitors; Humans; Lopinavir; Male; Meningeal Neoplasms; Meningioma; Middle Aged; Phosphorylation; Platelet-Derived Growth Factor; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-sis; Pyrimidinones; Signal Transduction; STAT3 Transcription Factor; TOR Serine-Threonine Kinases; Tumor Cells, Cultured

Topics: Aminohydrolases; Astrocytoma; Central Nervous System; Glioblastoma; Humans; Meningeal Neoplasms; Meningioma; Neoplasms; Phosphates; Pyrimidinones