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Oncogene Apr 2022Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, invasive cancer that comprise around 10% of all soft tissue sarcomas and develop in about 8-13% of... (Review)
Review
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, invasive cancer that comprise around 10% of all soft tissue sarcomas and develop in about 8-13% of patients with Neurofibromatosis Type 1. They are associated with poor prognosis and are the leading cause of mortality in NF1 patients. MPNSTs can also develop sporadically or following exposure to radiation. There is currently no effective targeted therapy to treat MPNSTs and surgical removal remains the mainstay treatment. Unfortunately, surgery is not always possible due to the size and location of the tumor, thus, a better understanding of MPNST initiation and development is required to design novel therapeutics. Here, we provide an overview of MPNST biology and genetics, discuss findings regarding the developmental origin of MPNST, and summarize the various model systems employed to study MPNST. Finally, we discuss current management strategies for MPNST, as well as recent developments in translating basic research findings into potential therapies.
Topics: Biology; Humans; Nerve Sheath Neoplasms; Neurofibromatosis 1; Neurofibrosarcoma; Sarcoma
PubMed: 35393544
DOI: 10.1038/s41388-022-02290-1 -
Cell Stem Cell Aug 2021NF1-associated malignant peripheral nerve sheath tumors (MPNSTs) are the major cause of mortality in neurofibromatosis. MPNSTs arise from benign peripheral nerve...
NF1-associated malignant peripheral nerve sheath tumors (MPNSTs) are the major cause of mortality in neurofibromatosis. MPNSTs arise from benign peripheral nerve plexiform neurofibromas that originate in the embryonic neural crest cell lineage. Using reporter transgenes that label early neural crest lineage cells in multiple NF1 MPNST mouse models, we discover and characterize a rare MPNST cell population with stem-cell-like properties, including quiescence, that is essential for tumor initiation and relapse. Following isolation of these cells, we derive a cancer-stem-cell-specific gene expression signature that includes consensus embryonic neural crest genes and identify Nestin as a marker for the MPNST cell of origin. Combined targeting of cancer stem cells along with antimitotic chemotherapy yields effective tumor inhibition and prolongs survival. Enrichment of the cancer stem cell signature in cognate human tumors supports the generality and relevance of cancer stem cells to MPNST therapy development.
Topics: Animals; Disease Models, Animal; Mice; Neoplasm Recurrence, Local; Neurofibromatosis 1; Neurofibrosarcoma
PubMed: 34010628
DOI: 10.1016/j.stem.2021.04.029 -
Clinical Cancer Research : An Official... Apr 2023Malignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas with limited treatment options and poor survival rates. About half of MPNST cases are associated...
PURPOSE
Malignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas with limited treatment options and poor survival rates. About half of MPNST cases are associated with the neurofibromatosis type 1 (NF1) cancer predisposition syndrome. Overexpression of TYK2 occurs in the majority of MPNST, implicating TYK2 as a therapeutic target.
EXPERIMENTAL DESIGN
The effects of pharmacologic TYK2 inhibition on MPNST cell proliferation and survival were examined using IncuCyte live cell assays in vitro, and downstream actions were analyzed using RNA-sequencing (RNA-seq), qPCR arrays, and validation of protein changes with the WES automated Western system. Inhibition of TYK2 alone and in combination with MEK inhibition was evaluated in vivo using both murine and human MPNST cell lines, as well as MPNST PDX.
RESULTS
Pharmacologic inhibition of TYK2 dose-dependently decreased proliferation and induced apoptosis over time. RNA-seq pathway analysis on TYK2 inhibitor-treated MPNST demonstrated decreased expression of cell cycle, mitotic, and glycolysis pathways. TYK2 inhibition resulted in upregulation of the MEK/ERK pathway gene expression, by both RNA-seq and qPCR array, as well as increased pERK1/2 levels by the WES Western system. The compensatory response was tested with dual treatment with TYK2 and MEK inhibitors, which synergistically decreased proliferation and increased apoptosis in vitro. Finally, combination therapy was shown to inhibit growth of MPNST in multiple in vivo models.
CONCLUSIONS
These data provide the preclinical rationale for the development of a phase I clinical trial of deucravacitinib and mirdametinib in NF1-assosciated MPNST.
Topics: Humans; Mice; Animals; Neurofibrosarcoma; Neurofibromatosis 1; Cell Line; Apoptosis; Mitogen-Activated Protein Kinase Kinases; Nerve Sheath Neoplasms; Cell Line, Tumor; TYK2 Kinase
PubMed: 36799629
DOI: 10.1158/1078-0432.CCR-22-3722 -
Cancer Discovery Mar 2023Malignant peripheral nerve sheath tumor (MPNST), an aggressive soft-tissue sarcoma, occurs in people with neurofibromatosis type 1 (NF1) and sporadically. Whole-genome...
UNLABELLED
Malignant peripheral nerve sheath tumor (MPNST), an aggressive soft-tissue sarcoma, occurs in people with neurofibromatosis type 1 (NF1) and sporadically. Whole-genome and multiregional exome sequencing, transcriptomic, and methylation profiling of 95 tumor samples revealed the order of genomic events in tumor evolution. Following biallelic inactivation of NF1, loss of CDKN2A or TP53 with or without inactivation of polycomb repressive complex 2 (PRC2) leads to extensive somatic copy-number aberrations (SCNA). Distinct pathways of tumor evolution are associated with inactivation of PRC2 genes and H3K27 trimethylation (H3K27me3) status. Tumors with H3K27me3 loss evolve through extensive chromosomal losses followed by whole-genome doubling and chromosome 8 amplification, and show lower levels of immune cell infiltration. Retention of H3K27me3 leads to extensive genomic instability, but an immune cell-rich phenotype. Specific SCNAs detected in both tumor samples and cell-free DNA (cfDNA) act as a surrogate for H3K27me3 loss and immune infiltration, and predict prognosis.
SIGNIFICANCE
MPNST is the most common cause of death and morbidity for individuals with NF1, a relatively common tumor predisposition syndrome. Our results suggest that somatic copy-number and methylation profiling of tumor or cfDNA could serve as a biomarker for early diagnosis and to stratify patients into prognostic and treatment-related subgroups. This article is highlighted in the In This Issue feature, p. 517.
Topics: Humans; Neurofibrosarcoma; Histones; DNA Methylation; Biomarkers, Tumor; Neurofibromatosis 1; Genomics; Nerve Sheath Neoplasms
PubMed: 36598417
DOI: 10.1158/2159-8290.CD-22-0786 -
Proceedings of the Royal Society of... Jan 1927
PubMed: 19985494
DOI: No ID Found -
International Journal of Molecular... Sep 2023Malignant peripheral nerve sheath tumors (MPNSTs) are deadly sarcomas, which desperately need effective therapies. Half of all MPNSTs arise in patients with... (Review)
Review
Malignant peripheral nerve sheath tumors (MPNSTs) are deadly sarcomas, which desperately need effective therapies. Half of all MPNSTs arise in patients with neurofibromatosis type I (NF1), a common inherited disease. NF1 patients can develop benign lesions called plexiform neurofibromas (PNFs), often in adolescence, and over time, some PNFs, but not all, will transform into MPNSTs. A deeper understanding of the molecular and genetic alterations driving PNF-MPNST transformation will guide development of more targeted and effective treatments for these patients. This review focuses on an oncogenic transcription factor, FOXM1, which is a powerful oncogene in other cancers but little studied in MPNSTs. Elevated expression of FOXM1 was seen in patient MPNSTs and correlated with poor survival, but otherwise, its role in the disease is unknown. We discuss what is known about FOXM1 in MPNSTs relative to other cancers and how FOXM1 may be regulated by and/or regulate the most commonly altered players in MPNSTs, particularly in the MEK and CDK4/6 kinase pathways. We conclude by considering FOXM1, MEK, and CDK4/6 as new, clinically relevant targets for MPNST therapy.
Topics: Adolescent; Humans; Cyclin-Dependent Kinase 4; Forkhead Box Protein M1; Mitogen-Activated Protein Kinase Kinases; Neurofibromatosis 1; Neurofibrosarcoma; Oncogenes; Sarcoma
PubMed: 37686402
DOI: 10.3390/ijms241713596 -
The Medical Journal of Malaysia Mar 2003Since January 1999, ten patients had undergone surgical treatment for metastatic bony lesions of proximal femur at this centre. Seven of these patients were treated for... (Review)
Review
Since January 1999, ten patients had undergone surgical treatment for metastatic bony lesions of proximal femur at this centre. Seven of these patients were treated for complete pathological fractures, one for impending fracture and one for revision of internal fixation and loosening of hemiarthroplasty. Primary malignancies were located in breast in four cases, prostate in three and one in lung, thyroid and neurofibrosarcoma. Two patients had died within six months after surgery, four after 1 year while the remaining four were still alive. The mean duration of survival was eleven months. Nine patients had been ambulating pain free and there were no failure of reconstruction.
Topics: Adult; Aged; Aged, 80 and over; Bone Neoplasms; Breast Neoplasms; Female; Femur; Humans; Lung Neoplasms; Male; Middle Aged; Neurofibrosarcoma; Prostatic Neoplasms; Radiography; Radionuclide Imaging; Thyroid Neoplasms
PubMed: 14556337
DOI: No ID Found -
Thorax Jul 1971Thirty-two mediastinal neural tumours were seen in the East Anglian Regional Thoracic Surgical Unit at Cambridge between October 1952 and July 1970. The descending order... (Review)
Review
Thirty-two mediastinal neural tumours were seen in the East Anglian Regional Thoracic Surgical Unit at Cambridge between October 1952 and July 1970. The descending order of frequency was neurofibroma, ganglioneuroma, neurilemmoma, neurofibrosarcoma, and neuroblastoma. The literature relating to these tumours is reviewed and the pathological and clinical complications encountered in this series and in the literature are described.
Topics: Adolescent; Adult; Age Factors; Child; Child, Preschool; Deglutition Disorders; Female; Ganglioneuroma; Horner Syndrome; Humans; Hypertension; Infant; Infant, Newborn; Lung Diseases; Lung Neoplasms; Male; Mediastinal Neoplasms; Mediastinum; Meningocele; Middle Aged; Neoplasm Regression, Spontaneous; Neoplasms, Nerve Tissue; Neurilemmoma; Neuroblastoma; Neurofibroma; Neurofibromatosis 1; Neurologic Manifestations; Osteoarthropathy, Secondary Hypertrophic; Pain; Paraganglioma, Extra-Adrenal; Pheochromocytoma; Sex Factors; Vitamin B 12
PubMed: 4327710
DOI: 10.1136/thx.26.4.392