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

Ciersten A. Burks, Steven D. Rhodes, Waylan K. Bessler, Shi Chen, Abbi Smith, Jeffrey R. Gehlhausen, Eric T. Hawley, Li Jiang, Xiaohong Li, Jin Yuan, Qingbo Lu, Max Jacobsen, George E. Sandusky, David R. Jones, D. Wade Clapp, Jaishri O. Blakeley

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

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 (pNF) 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 (GEMM) 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;PostnCreþ 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 that ketotifen has limited use as monotherapy to prevent or reduce pNF burden in the setting of Nf1 mutations.

Original languageEnglish (US)
Pages (from-to)2321-2330
Number of pages10
JournalMolecular cancer therapeutics
Volume18
Issue number12
DOIs
StatePublished - 2019

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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