Browsing by Subject "Neurofibroma"

Now showing 1 - 6 of 6
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    Cabozantinib for neurofibromatosis type 1-related plexiform neurofibromas: a phase 2 trial
    (Springer Nature, 2021-01) Fisher, Michael J.; Shih, Chie-Schin; Rhodes, Steven D.; Armstrong, Amy E.; Wolters, Pamela L.; Dombi, Eva; Zhang, Chi; Angus, Steven P.; Johnson, Gary L.; Packer, Roger J.; Allen, Jeffrey C.; Ullrich, Nicole J.; Goldman, Stewart; Gutmann, David H.; Plotkin, Scott R.; Rosser, Tena; Robertson, Kent A.; Widemann, Brigitte C.; Smith, Abbi E.; Bessler, Waylan K.; He, Yongzheng; Park, Su-Jung; Mund, Julie A.; Jiang, Li; Bijangi-Vishehsaraei, Khadijeh; Robinson, Coretta Thomas; Cutter, Gary R.; Korf, Bruce R.; Blakeley, Jaishri O.; Clapp, D. Wade; Pediatrics, School of Medicine
    Neurofibromatosis type 1 (NF1) plexiform neurofibromas (PNs) are progressive, multicellular neoplasms that cause morbidity and may transform to sarcoma. Treatment of Nf1fl/fl;Postn-Cre mice with cabozantinib, an inhibitor of multiple tyrosine kinases, caused a reduction in PN size and number and differential modulation of kinases in cell lineages that drive PN growth. Based on these findings, the Neurofibromatosis Clinical Trials Consortium conducted a phase II, open-label, nonrandomized Simon two-stage study to assess the safety, efficacy and biologic activity of cabozantinib in patients ≥16 years of age with NF1 and progressive or symptomatic, inoperable PN ( NCT02101736 ). The trial met its primary outcome, defined as ≥25% of patients achieving a partial response (PR, defined as ≥20% reduction in target lesion volume as assessed by magnetic resonance imaging (MRI)) after 12 cycles of therapy. Secondary outcomes included adverse events (AEs), patient-reported outcomes (PROs) assessing pain and quality of life (QOL), pharmacokinetics (PK) and the levels of circulating endothelial cells and cytokines. Eight of 19 evaluable (42%) trial participants achieved a PR. The median change in tumor volume was 15.2% (range, +2.2% to -36.9%), and no patients had disease progression while on treatment. Nine patients required dose reduction or discontinuation of therapy due to AEs; common AEs included gastrointestinal toxicity, hypothyroidism, fatigue and palmar plantar erythrodysesthesia. A total of 11 grade 3 AEs occurred in eight patients. Patients with PR had a significant reduction in tumor pain intensity and pain interference in daily life but no change in global QOL scores. These data indicate that cabozantinib is active in NF1-associated PN, resulting in tumor volume reduction and pain improvement.
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    Erk1 and Erk2 in hematopoiesis, mast cell function, and the management of Nf1-associated leukemia and tumors
    (2012-03) Staser, Karl W.; Clapp, D. Wade; Yang, Feng-Chun; Goebl, Mark, 1958-; Harrington, Maureen A.
    Neurofibromatosis type 1 is a genetic disease that results from either heritable or spontaneous autosomal dominant mutations in the NF1 gene, which encodes a protein serving, at least in part, to accelerate the intrinsic hydrolysis of active Ras-GTP to inactive Ras-GDP. A second-hit NF1 mutation precedes predominant NF1 neoplasms, including juvenile myelomoncytic leukemia (JMML) and plexiform neurofibroma formation, potentially fatal conditions with no medical therapy. While NF1 loss of heterozygosity (LOH) in myeloid progenitor cells sufficiently engenders leukemogenesis, plexiform neurofibroma formation depends on LOH in Schwann cells and Nf1 heterozygosity in the hematopoietic system. Specifically, recruited Nf1+/- mast cells accelerate tumorigenesis through secreted cytokines and growth factors. Nf1+/- mast cells depend upon deregulated signaling in c-kit pathways, a receptor system conserved in hematopoietic stem cells (HSCs). Accordingly, Nf1-/- myeloid progenitor cells, which can induce a JMML-like disease in mice, also demonstrate deregulated c-kit receptor signaling. C-kit-activated Nf1+/- mast cells and Nf1-/- myeloid progenitors both show increased latency and potency of active Erk1 and Erk2, the principal cytosolic-to-nuclear effectors of canonical Ras-Raf-Mek signaling. Thus, Erk represents a potential regulator of leukemogenesis and tumor-associated inflammation. However, single and combined Erk1 and Erk2 roles in HSC function, myelopoiesis, and mature mast cell physiology remain unknown, and recent hematopoietic studies relying on chemical Mek-Erk inhibitors have produced conflicting results. Here, we show that hematopoietic stability, myelopoiesis, and mast cell generation require Erk1 or Erk2, but individual isoforms are largely dispensable. Principally, Erk-disrupted hematopoietic stem cells incorporate BrdU but are incapable of dividing, a novel and cell type-specific Erk function. Similarly, mast cell proliferation requires Erk but cytokine production proceeds through other pathways, elucidating molecule-specific functions within the c-kit cascade. Based on these findings, we have reduced tumor mast cell infiltration by treating genetically-engineered tumor model mice with PD0325901, a preclinical Mek-Erk inhibitor. Moreover, we have devised a quadruple transgenic HSC transplantation model to examine dual Erk disruption in the context of Nf1 nullizygosity, testing whether diseased hematopoiesis requires Erk. These insights illuminate cell-specific Erk functions in normal and Nf1-deficient hematopoiesis, informing the feasibility of targeting Mek-Erk in NF1-associated disease.
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    Existing and Developing Preclinical Models for Neurofibromatosis Type 1–Related Cutaneous Neurofibromas
    (Elsevier, 2023) Staedtke, Verena; Topilko, Piotr; Le, Lu Q.; Grimes, Kevin; Largaespada, David A.; Cagan, Ross L.; Steensma, Matthew R.; Stemmer-Rachamimov, Anat; Blakeley, Jaishri O.; Rhodes, Steven D.; Ly, Ina; Romo, Carlos G.; Lee, Sang Y.; Serra, Eduard; Pediatrics, School of Medicine
    Neurofibromatosis type 1 (NF1) is caused by a nonfunctional copy of the NF1 tumor suppressor gene that predisposes patients to the development of cutaneous neurofibromas (cNFs), the skin tumor that is the hallmark of this condition. Innumerable benign cNFs, each appearing by an independent somatic inactivation of the remaining functional NF1 allele, form in nearly all patients with NF1. One of the limitations in developing a treatment for cNFs is an incomplete understanding of the underlying pathophysiology and limitations in experimental modeling. Recent advances in preclinical in vitro and in vivo modeling have substantially enhanced our understanding of cNF biology and created unprecedented opportunities for therapeutic discovery. We discuss the current state of cNF preclinical in vitro and in vivo model systems, including two- and three-dimensional cell cultures, organoids, genetically engineered mice, patient-derived xenografts, and porcine models. We highlight the models' relationship to human cNFs and how they can be used to gain insight into cNF development and therapeutic discovery.
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    Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype-phenotype correlation
    (Springer Nature, 2019-04) Koczkowska, Magdalena; Callens, Tom; Gomes, Alicia; Sharp, Angela; Chen, Yunjia; Hicks, Alesha D.; Aylsworth, Arthur S.; Azizi, Amedeo A.; Basel, Donald G.; Bellus, Gary; Bird, Lynne M.; Blazo, Maria A.; Burke, Leah W.; Cannon, Ashley; Collins, Felicity; DeFilippo, Colette; Denayer, Ellen; Digilio, Maria C.; Dills, Shelley K.; Dosa, Laura; Greenwood, Robert S.; Griffis, Cristin; Gupta, Punita; Hachen, Rachel K.; Hernández-Chico, Concepción; Janssens, Sandra; Jones, Kristi J.; Jordan, Justin T.; Kannu, Peter; Korf, Bruce R.; Lewis, Andrea M.; Listernick, Robert H.; Lonardo, Fortunato; Mahoney, Maurice J.; Ojeda, Mayra Martinez; McDonald, Marie T.; McDougall, Carey; Mendelsohn, Nancy; Miller, David T.; Mori, Mari; Oostenbrink, Rianne; Perreault, Sebastién; Pierpont, Mary Ella; Piscopo, Carmelo; Pond, Dinel A.; Randolph, Linda M.; Rauen, Katherine A.; Rednam, Surya; Rutledge, S. Lane; Saletti, Veronica; Schaefer, G. Bradley; Schorry, Elizabeth K.; Scott, Daryl A.; Shugar, Andrea; Siqveland, Elizabeth; Starr, Lois J.; Syed, Ashraf; Trapane, Pamela L.; Ullrich, Nicole J.; Wakefield, Emily G.; Walsh, Laurence E.; Wangler, Michael F.; Zackai, Elaine; Claes, Kathleen B. M.; Wimmer, Katharina; van Minkelen, Rick; De Luca, Alessandro; Martin, Yolanda; Legius, Eric; Messiaen, Ludwine M.; Neurology, School of Medicine
    PURPOSE: Neurofibromatosis type 1 (NF1) is characterized by a highly variable clinical presentation, but almost all NF1-affected adults present with cutaneous and/or subcutaneous neurofibromas. Exceptions are individuals heterozygous for the NF1 in-frame deletion, c.2970_2972del (p.Met992del), associated with a mild phenotype without any externally visible tumors. METHODS: A total of 135 individuals from 103 unrelated families, all carrying the constitutional NF1 p.Met992del pathogenic variant and clinically assessed using the same standardized phenotypic checklist form, were included in this study. RESULTS: None of the individuals had externally visible plexiform or histopathologically confirmed cutaneous or subcutaneous neurofibromas. We did not identify any complications, such as symptomatic optic pathway gliomas (OPGs) or symptomatic spinal neurofibromas; however, 4.8% of individuals had nonoptic brain tumors, mostly low-grade and asymptomatic, and 38.8% had cognitive impairment/learning disabilities. In an individual with the NF1 constitutional c.2970_2972del and three astrocytomas, we provided proof that all were NF1-associated tumors given loss of heterozygosity at three intragenic NF1 microsatellite markers and c.2970_2972del. CONCLUSION: We demonstrate that individuals with the NF1 p.Met992del pathogenic variant have a mild NF1 phenotype lacking clinically suspected plexiform, cutaneous, or subcutaneous neurofibromas. However, learning difficulties are clearly part of the phenotypic presentation in these individuals and will require specialized care.
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    RAS Signaling Gone Awry in the Skin: The Complex Role of RAS in Cutaneous Neurofibroma Pathogenesis, Emerging Biological Insights
    (Elsevier, 2023) Rhodes, Steven D.; McCormick, Frank; Cagan, Ross L.; Bakker, Annette; Staedtke, Verena; Ly, Ina; Steensma, Matthew R.; Lee, Sang Y.; Romo, Carlos G.; Blakeley, Jaishri O.; Sarin, Kavita Y.; Pediatrics, School of Medicine
    Cutaneous neurofibromas (cNFs) are the most common tumor in people with the rasopathy neurofibromatosis type 1. They number in hundreds or even thousands throughout the body, and currently, there are no effective interventions to prevent or treat these skin tumors. To facilitate the identification of novel and effective therapies, essential studies including a more refined understanding of cNF biology and the role of RAS signaling and downstream effector pathways responsible for cNF initiation, growth, and maintenance are needed. This review highlights the current state of knowledge of RAS signaling in cNF pathogenesis and therapeutic development for cNF treatment.
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    Spatial Gene-Expression Profiling Unveils Immuno-oncogenic Programs of NF1-Associated Peripheral Nerve Sheath Tumor Progression
    (American Association for Cancer Research, 2024) Mitchell, Dana K.; Burgess, Breanne; White, Emily E.; Smith, Abbi E.; Potchanant, Elizabeth A. Sierra; Mang, Henry; Hickey, Brooke E.; Lu, Qingbo; Qian, Shaomin; Bessler, Waylan; Li, Xiaohong; Jiang, Li; Brewster, Kylee; Temm, Constance; Horvai, Andrew; Albright, Eric A.; Fishel, Melissa L.; Pratilas, Christine A.; Angus, Steven P.; Clapp, D. Wade; Rhodes, Steven D.; Pediatrics, School of Medicine
    Purpose: Plexiform neurofibromas (PNF) are benign peripheral nerve sheath tumors (PNST) associated with neurofibromatosis type 1 (NF1). Despite similar histologic appearance, these neoplasms exhibit diverse evolutionary trajectories, with a subset progressing to malignant peripheral nerve sheath tumor (MPNST), the leading cause of premature death in individuals with NF1. Malignant transformation of PNF often occurs through the development of atypical neurofibroma (ANF) precursor lesions characterized by distinct histopathologic features and CDKN2A copy-number loss. Although genomic studies have uncovered key driver events promoting tumor progression, the transcriptional changes preceding malignant transformation remain poorly defined. Experimental design: Here we resolve gene-expression profiles in PNST across the neurofibroma-to-MPNST continuum in NF1 patients and mouse models, revealing early molecular features associated with neurofibroma evolution and transformation. Results: Our findings demonstrate that ANF exhibit enhanced signatures of antigen presentation and immune response, which are suppressed as malignant transformation ensues. MPNST further displayed deregulated survival and mitotic fidelity pathways, and targeting key mediators of these pathways, CENPF and BIRC5, disrupted the growth and viability of human MPNST cell lines and primary murine Nf1-Cdkn2a-mutant Schwann cell precursors. Finally, neurofibromas contiguous with MPNST manifested distinct alterations in core oncogenic and immune surveillance programs, suggesting that early molecular events driving disease progression may precede histopathologic evidence of malignancy. Conclusions: If validated prospectively in future studies, these signatures may serve as molecular diagnostic tools to augment conventional histopathologic diagnosis by identifying neurofibromas at high risk of undergoing malignant transformation, facilitating risk-adapted care.