Document text
Principal Investigator: Angela Christine Hirbe
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2024
Award: $488,097
Funding agency: National Institute of Neurological Disorders and Stroke
Project Summary
Neurofibromatosis type 1 (NF1) is a common neurogenetic cancer predisposition syndrome, affecting 1 in
3,000 individuals worldwide. While most of the tumors are benign neoplasms (neurofibromas, low-grade
gliomas), 10-13% of patients will develop an aggressive sarcoma, termed a malignant peripheral nerve sheath
tumor (MPNST). Composed of high-grade neoplastic Schwann cells, MPNST most often arise from a benign
precursor lesion, such as plexiform neurofibroma (PN). Unfortunately, even with aggressive multi-modality
therapy, these cancers recur in >50% of individuals, and most patients die within five years of diagnosis. For
this reason, there is an unmet need for better therapeutic modalities. To identify novel targets, we generated a
series of patient-derived xenografts (PDX) lines that more accurately reflect the molecular heterogeneity of
human MPNSTs. Using these PDX lines, we showed that MPNST exhibit a high degree of aneuploidy and
harbor gains involving the long arm of chromosome 8 (Chr8q). Detailed analysis of Chr8q genes revealed that
UBR5 is the most highly upregulated gene in MPNST and that UBR5 genetic knockdown (KD) decreased
MPNST proliferation, survival, and migration. Based on these exciting data, we hypothesize that UBR5 is a
key driver of MPNST pathogenesis and in part responsible for Chr8 gain-mediated MPNST malignant
progression. In this proposal, we will: (1) Define when in MPNST progression Chr8q gain occurs and if UBR5
expression through this molecular event correlates with worse overall survival. (2) Utilize a recently developed
human induced pluripotent stem cell plexiform model and a murine Nf1 mutant plexiform neurofibroma-prone
strain that develops MPNST following lentiviral manipulation of other genomic drivers to determine the
sufficiency of UBR5 to promote MPNST formation. (3) Determine the mechanism of action of UBR5 in MPNST
including how UBR5 regulates cell survival and whether its role is dependent on its E3 ubiquitin ligase activity.
The experiments outlined in this proposal will provide a deeper understanding of the molecular pathogenesis of
MPNST, which is required to uncover new opportunities for the development of novel therapeutic strategies
that may improve clinical outcomes.
Terms: <Aberrant Chromosome><Address><Affect><Aneuploid><Aneuploidy><Apoptotic><Assay><Attention><Benign><Bioassay><Biological><Biological Assay><Cancer Treatment><Cancers><Cell Body><Cell Growth in Number><Cell Multiplication><Cell Proliferation><Cell Survival><Cell Viability><Cells><Cellular Expansion><Cellular Growth><Cellular Proliferation><Chromosomal Aberrations><Chromosomal Abnormalities><Chromosomal Alterations><Chromosome 8><Chromosome Aberrations><Chromosome Alterations><Chromosome Anomalies><Chromosome Arm><Chromosome abnormality><Clinical><Collection><Coupling><Cytogenetic Aberrations><Cytogenetic Abnormalities><DNA Alteration><DNA Sequence Alteration><DNA mutation><Data><Development><Diagnosis><E3 Ligase><E3 Ubiquitin Ligase><Early Diagnosis><Elephantiasis Neuromatosis><Event><Exhibits><FISH Technic><FISH Technique><FISH analysis><FISH assay><Fluorescence In Situ Hybridization><Fluorescent in Situ Hybridization><Generalized Growth><Genes><Genetic><Genetic mutation><Genomics><Glial Cell Tumors><Glial Neoplasm><Glial Tumor><Glioma><Goals><Growth><Heterogeneity><Human><In Vitro><Individual><Injections><Lesion><Malignant><Malignant - descriptor><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Peripheral Nerve Sheath Tumor><Malignant Schwannoma><Malignant Soft Tissue Neoplasm><Malignant Tumor><Mediating><Mice><Mice Mammals><Modality><Modeling><Modern Man><Molecular><Murine><Mus><NF-1><NF-1 Protein><NF-1 encoded protein><NF1><NF1 GRP><NF1 Protein><NF1 gene><NF1-GAP-Related Protein><Neoplasms><Neoplastic Schwann Cell><Network Analysis><Neurofibromatosis 1><Neurofibromatosis 1 Genes><Neurofibromatosis I><Neurofibromatosis Type 1 Gene Product><Neurofibromatosis Type 1 Protein><Neurofibromin><Neurofibromin 1><Neurofibrosarcoma><Neurogenic Sarcoma><Neuroglial Neoplasm><Neuroglial Tumor><Oncogenesis><Oncogenic><Outcome><Outcome Study><PDX model><Pachydermatocele><Pathogenesis><Pathway Analysis><Pathway interactions><Patient derived xenograft><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Peripheral Neurofibromatosis><Plexiform Neurofibroma><Plexiform Neuromas><Proliferating><RNA Seq><RNA sequencing><RNAseq><Recklinghausen Disease of Nerve><Recklinghausen's disease><Recklinghausen's neurofibromatosis><Recurrent Malignant Neoplasm><Recurrent Malignant Tumor><Recurrent Neoplasm><Recurrent tumor><Regulation><Risk Assessment><Role><Sarcoma><Sequence Alteration><Series><Solid Neoplasm><Solid Tumor><Syndrome><System><Testing><Therapeutic><Tissue Growth><Tumor Biology><Tumor Cell Line><Tumor Royale><Type 1 Neurofibromatosis><Type I Neurofibromatosis><Ubiquitin Protein Ligase><Ubiquitin-Protein Ligase Complexes><Ubiquitin-Protein Ligase E3><Up-Regulation><Upregulation><Work><anti-cancer therapy><biologic><cancer predisposition><cancer progression><cancer recurrence><cancer therapy><cancer-directed therapy><cell growth><chromosomal defect><chromosome 8 gain><chromosome defect><combination cancer therapy><develop therapy><developmental><early detection><effective therapy><effective treatment><entire genome><experiment><experimental research><experimental study><experiments><full genome><genome sequencing><genomic alteration><glial-derived tumor><hiPSC><human iPS><human iPSC><human induced pluripotent cell><human induced pluripotent stem cells><human inducible stem cells><improved><in vivo><induced human pluripotent stem cells><intervention development><knock-down><knockdown><malignancy><malignant soft tissue tumor><migration><multi-modal cancer therapy><multi-modal neoplasm therapy><multimodality cancer therapy><multimodality neoplasm therapy><mutant><neoplasia><neoplasm progression><neoplasm recurrence><neoplasm/cancer><neoplastic growth><neoplastic progression><neurofibroma><neurofibromatosis type 1 gene><neurofibromatosis type 1 protein/gene><neurogenetics><neuroglia neoplasm><neuroglia tumor><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><nf 1 Genes><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><ontogeny><pathway><patient derived xenograft model><patient oriented outcomes><patient population><prognostic><prognostication><sciatic nerve><shRNA><short hairpin RNA><small hairpin RNA><social role><therapeutic target><therapy development><tool><transcriptome sequencing><transcriptomic sequencing><treatment development><tumor><tumor progression><tumorigenesis><ubiquitin-protein ligase><von Recklinghausen Disease><whole genome>