Browsing by Subject "plexiform neurofibroma"

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    Early administration of imatinib mesylate reduces plexiform neurofibroma tumor burden with durable results after drug discontinuation in a mouse model of neurofibromatosis type 1
    (Wiley, 2020-05-27) Armstrong, Amy E.; Rhodes, Steven D.; Smith, Abbi; Chen, Shi; Bessler, Waylan; Ferguson, Michael J.; Jiang, Li; Li, Xiaohong; Yuan, Jin; Yang, Xianlin; Yang, Feng-Chun; Robertson, Kent A.; Ingram, David A.; Blakeley, Jaishri O.; Clapp, D. Wade; Pediatrics, School of Medicine
    BACKGROUND Neurofibromatosis type 1 (NF1) is a common genetic disorder characterized by plexiform neurofibromas (pNF), which are thought to be congenital tumors that arise in utero and enlarge throughout life. Genetic studies in murine models delineated an indispensable role for the stem cell factor (SCF)/c-kit pathway in pNF initiation and progression. A subsequent phase 2 clinical trial using imatinib mesylate to inhibit SCF/c-kit demonstrated tumor shrinkage in a subset of pre-existing pNF, however imatinib’s role on preventing pNF development has yet to be explored. PROCEDURE We evaluated the effect of imatinib dosed at 10–100 mg/kg/day for 12 weeks to 1-month old Nf1flox/flox;PostnCre(+) mice, prior to onset of pNF formation. To determine durability of response, we then monitored for pNF growth at later time points, comparing imatinib to vehicle treated mice. We assessed gross and histopathological analysis of tumor burden. RESULTS Imatinib administered preventatively led to a significant decrease in pNF number, even at doses as low as 10 mg/kg/day. Tumor development continued to be significantly inhibited after cessation of imatinib dosed at 50 and 100 mg/kg/day. In the cohort of treated mice that underwent prolonged follow-up, the size of residual tumors was significantly reduced as compared to age-matched littermates that received vehicle control. CONCLUSIONS Early administration of imatinib inhibits pNF genesis in vivo and effects are sustained after discontinuation of therapy. These findings may guide clinical use of imatinib in young NF1 patients prior to substantial development of pNF.
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    Ketotifen Modulates Mast Cell Chemotaxis to Kit-Ligand, but Does Not Impact Mast Cell Numbers, Degranulation, or Tumor Behavior in Neurofibromas of Nf1-Deficient Mice
    (American Association for Cancer Research, 2019-12-01) Burks, Ciersten A.; Rhodes, Steven D.; Bessler, Waylan K.; Chen, Shi; Smith, Abbi; Gehlhausen, Jeffrey R.; Hawley, Eric T.; Jiang, Li; Li, Xiaohong; Yuan, Jin; Lu, Qingbo; Jacobsen, Max; Sandusky, George E.; Jones, David R.; Clapp, D. Wade; Blakeley, Jaishri O.; Pediatrics, School of Medicine
    Neurofibromatosis Type 1 (NF1) is one of the most common genetic tumor predisposition syndromes in humans. Mutant NF1 results in dysregulated RAS allowing neoplasms throughout the neuroaxis. Plexiform neurofibromas (pNFs) afflict up to 50% of patients with NF1. They are complex tumors of the peripheral nerve that cause major morbidity via nerve dysregulation and mortality via conversion to malignant sarcoma. Genetically engineered mouse models (GEMMs) of NF1 provide valuable insights for the identification of therapies that have utility in people with pNF. Preclinical studies in GEMMs implicate mast cells and the c-Kit/Kit ligand pathway in pNF tumorigenesis. Kit ligand is a potent chemokine secreted by tumorigenic, Nf1-deficient Schwann cells. Ketotifen is an FDA-approved drug for the treatment of allergic conjunctivitis and asthma that promotes mast cell stabilization and has been used in prior case studies to treat or prevent pNFs. This study investigated the effect of ketotifen on mast cell infiltration and degranulation in the presence and absence of Kit ligand provocation and the effect of ketotifen on shrinking or preventing pNF formation in the Nf1flox/flox;PostnCre+ GEMM. Ketotifen decreased mast cell infiltration in response to exogenous Kit ligand administration, but did not affect mast cell degranulation. Importantly, ketotifen did not reduce mast cells numbers or activity in pNF and did not prevent pNF formation or decrease the volume of established pNF despite administration of pharmacologically active doses. These findings suggest ketotifen has limited use as monotherapy to prevent or reduce pNF burden in the setting of Nf1 mutations.