pyrimidinones and Rhabdoid-Tumor

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

Atypical teratoid/rhabdoid tumors (AT/RT) are rare, but highly aggressive. These entities are of embryonal origin occurring in the central nervous system (CNS) of young children. Molecularly these tumors are driven by a single hallmark mutation, resulting in inactivation of SMARCB1 or SMARCA4. Additionally, activation of the MAPK signaling axis and preclinical antitumor efficacy of its inhibition have been described in AT/RT.. We established and validated a patient-derived neurosphere culture and xenograft model of sonic hedgehog (SHH) subtype AT/RT, at diagnosis and relapse from the same patient. We set out to study the vascular phenotype of these tumors to evaluate the integrity of the blood-brain barrier (BBB) in AT/RT. We also used the model to study combined mitogen-activated protein kinase kinase (MEK) and maternal embryonic leucine zipper kinase (MELK) inhibition as a therapeutic strategy for AT/RT.. We found MELK to be highly overexpressed in both patient samples of AT/RT and our primary cultures and xenografts. We identified a potent antitumor efficacy of the MELK inhibitor OTSSP167, as well as strong synergy with the MEK inhibitor trametinib, against primary AT/RT neurospheres. Additionally, vascular phenotyping of AT/RT patient material and xenografts revealed significant BBB aberrancies in these tumors. Finally, we show in vivo efficacy of the non-BBB penetrable drugs OTSSP167 and trametinib in AT/RT xenografts, demonstrating the therapeutic implications of the observed BBB deficiencies and validating MEK/MELK inhibition as a potential treatment.. Altogether, we developed a combination treatment strategy for AT/RT based on MEK/MELK inhibition and identify therapeutically exploitable BBB deficiencies in these tumors.

Topics: Animals; Blood-Brain Barrier; Cell Proliferation; Female; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Mitogen-Activated Protein Kinase Kinases; Naphthyridines; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Pyridones; Pyrimidinones; Rhabdoid Tumor; Spheroids, Cellular; Teratoma; Tumor Cells, Cultured; Xenograft Model Antitumor Assays