Platelet-derived growth factor receptor inhibition to treat idiopathic hypereosinophilic syndrome.

Abstract

Hypereosinophilic syndrome (HES) is a heterogeneous group of rare disorders characterized by peripheral blood and tissue eosinophilia leading to end-organ damage. Hypereosinophilic syndrome can be fatal, particularly in patients with endomyocardial fibrosis, and treatment has traditionally been palliative or preventive. The disease shares features with myeloproliferative disorders, such as chronic myeloid leukemia, including responsiveness to hydroxyurea and interferon. The tyrosine kinase inhibitor imatinib, a highly effective treatment for chronic myeloid leukemia, has shown efficacy in normalizing eosinophil counts and resolving signs and symptoms in some HES patients. Fusion of the Fip1-like 1 gene (FIP1L1) and the platelet-derived growth factor receptor alpha gene (PDGFRA) was discovered in the majority of patients with imatinib-sensitive HES, and all patients with the fusion responded to imatinib. The product of this fusion gene, FIP1L1-PDGFRalpha, is a constitutively active protein-tyrosine kinase capable of transforming hematopoietic cells. The efficacy of relatively low imatinib concentrations in HES, mediated by inhibition of FIP1L1-PDGFRalpha kinase activity, causally implicates FIP1L1-PDGFRA in the pathogenesis in certain HES patients.

• Authors: Richard M Stone, D Gary Gilliland, Amy D Klion
• Journal: Seminars in oncology (Semin Oncol) Vol. 31 Issue 2 Suppl 6 Pg. 12-7 (Apr 2004) ISSN: 0093-7754 [Print] United States
• PMID: 15175999 (Publication Type: Journal Article, Review)

Chemical References

• Benzamides
• Enzyme Inhibitors
• Oncogene Proteins, Fusion
• Piperazines
• Pyrimidines
• Imatinib Mesylate
• Protein-Tyrosine Kinases
• Receptors, Platelet-Derived Growth Factor
• Monomeric GTP-Binding Proteins

Topics

• Benzamides
• Enzyme Inhibitors (therapeutic use)
• Humans
• Hypereosinophilic Syndrome (drug therapy, genetics)
• Imatinib Mesylate
• Monomeric GTP-Binding Proteins (genetics)
• Oncogene Proteins, Fusion
• Piperazines (therapeutic use)
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Pyrimidines (therapeutic use)
• Receptors, Platelet-Derived Growth Factor (antagonists & inhibitors, genetics)