Project description:Malignant peripheral nerve sheath tumors (MPNSTs) are the leading cause of premature death for patients with Neurofibromatosis type 1 and no approved targeted therapies are available. Benign plexiform neurofibromas have been successfully treated with selumetinib, a MEK inhibitor, but after progression to MPNST, MEK inhibition alone is not effective. Frequently, adaptive responses to single agent targeted inhibitors invokes alterations in receptor tyrosine kinase expression and feedback regulation that leads to inhibitor bypass. Here, the effects of SHP099, an inhibitor of the protein-tyrosine phosphatase SHP2 (encoded by the PTPN11 gene) was tested alone and in combination with trametinib (MEKi) in an NF1 MPNST patient derived xenograft model (PDX4) treated with SHP099, hydroxychloroquine (HCQ) or the combination. Kinase enrichment proteomic analysis was performed using tumor tissue treated with SHP099, hydroxychloroquine (HCQ) or the combination to evaluate the effects on the functional kinome.
Project description:Malignant peripheral nerve sheath tumors (MPNSTs) are the leading cause of premature death for patients with Neurofibromatosis type 1 and no approved targeted therapies are available. Benign plexiform neurofibromas have been successfully treated with selumetinib, a MEK inhibitor, but after progression to MPNST, MEK inhibition alone is not effective. Frequently, adaptive responses to single agent targeted inhibitors invokes alterations in receptor tyrosine kinase expression and feedback regulation that leads to inhibitor bypass. Here, the effects of SHP099, an inhibitor of the protein-tyrosine phosphatase SHP2 (encoded by the PTPN11 gene) was tested alone and in combination with trametinib (MEKi) in an orthotopic implantation murine model of NF1 MPNST with defined genotype (NP, Nf1-/-;Trp53-/-). Kinase enrichment proteomic analysis was performed using tumor tissue from vehicle, SHP099, trametinib, or trametinib and SHP099 in combination for 5 or 21 days to evaluate the effects on the functional kinome.
Project description:Malignant peripheral nerve sheath tumors (MPNSTs) are the leading cause of premature death for patients with Neurofibromatosis type 1 and no approved targeted therapies are available. Benign plexiform neurofibromas have been successfully treated with selumetinib, a MEK inhibitor, but after progression to MPNST, MEK inhibition alone is not effective. Frequently, adaptive responses to single agent targeted inhibitors invokes alterations in receptor tyrosine kinase expression and feedback regulation that leads to inhibitor bypass. Here, the effects of SHP099, an inhibitor of the protein-tyrosine phosphatase SHP2 (encoded by the PTPN11 gene) was tested alone and in combination with trametinib (MEKi) in an orthotopic implantation murine model of NF1 MPNST with defined gentotype (NI, Nf1-/-;Ink4a/Arf-/-). Kinase enrichment proteomic analysis was performed using tumor tissue from vehicle, SHP099, or trametinib and SHP099 in combination for 5, 15, or 28 days to evaluate the effects on the functional kinome.
Project description:<p>Malignant peripheral nerve sheath tumors (MPNSTs) are a group of highly aggressive soft tissue sarcomas that may occur sporadically, in association with neurofibromatosis type I (NF1-associated), or after radiotherapy (RT-associated). We utilized comprehensive genomic approaches and identified recurrent loss-of-function somatic alterations in the Polycomb repressive complex 2 (PRC2) core components EED or SUZ12. Genetic loss of either of these two genes results in complete loss of H3K27me3 and aberrant transcriptional programming in the affected tumors.</p>
Project description:The goal of this study was to determine the distribution of H3K27me3 in rat peripheral nerve, which is formed by PRC2, polycomb repressive complex 2.
Project description:Malignant peripheral nerve sheath tumors (MPNSTs) are the leading cause of premature death for patients with Neurofibromatosis type 1 and no approved targeted therapies are available. Transformation from Nf1-null benign plexiform neurofibromas is driven by the loss of the Cdkn2a (Arf) locus. Here, genetically engineered mouse models with combined Nf1 flox/flox and Arf flox/flox alleles were used (crossed with Postn-Cre+ mice). Tissue from MPNSTs that form in the Nf1-/-;Arf-/- setting were used for mRNA sequencing and compared to benign plexiform neurofibroma tissue (Nf1-/- from Nf1 flox/flox; Postn-Cre+ mice, GSE213789) to identify transcriptome signatures from MPNST and compare them to benign plexiform neurofibroma.
