Potential role of enzastaurin in the treatment of patients with relapsed or refractory advanced cutaneous T-cell lymphomas: a review
Deborah A Katz, Janet MD Plate, Sunita Nathan, Lydia Usha
Division of Hematology and Oncology, Rush University Medical Center, Chicago, IL, USA
Abstract: Cutaneous T-cell lymphomas (CTCLs) are rare extranodal non-Hodgkin lymphomas characterized by neoplastic T-lymphocyte accumulation in the skin. The two most common types of CTCLs are mycosis fungoides and the leukemic variant, Sézary syndrome. Prognosis of CTCLs depends on the stage, with a poor prognosis in advanced-stage disease. A number of agents have recently been developed for the treatment of CTCLs: chemotherapeutic agents such as pralatrexate, interferon-alpha, retinoids such as bexarotene, monoclonal antibodies such as alemtuzumab, and histone deacetylase inhibitors such as vorinostat and romidepsin. Nevertheless, there is no cure for CTCLs except for allogeneic stem cell transplant. A promising new drug is enzastaurin. Enzastaurin is a novel serine/threonine kinase inhibitor that binds to protein kinase
C-β (PKC-β) and inhibits the phosphoinositide-3 kinase (PI3K)/AKT/phosphatase and tensin homolog (PTEN) signaling pathway. Enzastaurin induces apoptosis and inhibits angiogenesis; it was also shown to suppress growth of CTCL cell lines in vitro. Given its low toxicity, enzastaurin has been tested against both solid tumors and hematologic malignancies. This article is focused on the potential role of enzastaurin in the treatment of CTCLs. A phase II multicenter trial evaluated enzastaurin monotherapy in patients with CTCLs. However, the results from this study were disappointing, demonstrating that enzastaurin had only modest clinical activity. Hence, enzastaurin is not currently developed for treating CTCLs. Potential strategies to improve enzastaurin efficacy against CTCLs are discussed: validation of enzastaurin targets such as PKC-β expression in CTCL lesions and or/blood; measurement of serum vascular endothelial growth factor levels; dose optimization; combining enzastaurin with other antiangiogenic agents, or glycogen synthase kinase inhibitors, or mammalian target of rapamycin (mTOR) inhibitors. Ultimately, developing more potent inhibitors of PKC-β and PI3K/AKT/PTEN/mTOR signaling pathways may be necessary to improve clinical outcomes in CTCLs.
Keywords: cutaneous T-cell lymphomas, enzastaurin, PKC-β inhibitors, serine/threonine kinase inhibitors, PI3K/AKT/PTEN pathway
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