Preclinical and clinical applications of enzastaurin in the treatment of malignant gliomas

Radiotherapy is essential in the treatment of malignant gliomas. However, it enhances the invasion of glioma cells and the secretion of vascular endothelial growth factor (VEGF) in experimental gliomas. We therefore assessed the combined effects of the protein kinase C inhibitor enzastaurin and radiotherapy in vitro and in vivo. The combination of enzastaurin and irradiation enhanced apoptosis in glioma cells in vitro. Basal and irradiation-induced secretion of VEGF were reduced by treatment with enzastaurin. Moreover, enzastaurin was not neurotoxic as assessed by the treatment of rat cerebellar granule neurons. Combining irradiation and enzastaurin prolonged the survival of orthotopic LNT-229 glioma-bearing mice in vivo and reduced tumor volumes, irradiation-induced tumor satellite formation, irradiation-induced up-regulation of VEGF-expression as well as microvessel densitiy in vivo. Taken together, these preclinical data demonstrate a synergistic anti-glioma activity of irradiation and enzastaurin without neurotoxicity. These data make enzastaurin an attractive radiosensitizing agent.

A clinical phase III trial was initiated in March 2006 to compare enzastaurin alone with CCNU alone in recurrent glioblastomas. After interim analysis, further recruitment of patients was stopped. Patients who were already enrolled could continue with the respective treatment. Further results of this study will be presented.

Based on the preclinical observations, and because a targeted agent most likely requires a further cytotoxic regimen, a phase I/II trial of enzastaurin plus radiotherapy will be initiated in 2007 in a cohort of glioblatoma patients not likely to benefit from alkylating agents. To select these patients the promoter methylation status of the methyl -guanine methyltransferase (MGMT) gene will be assessed. Patients with a methylated MGMT promoter will receive standard radiochemotherapy with temozolomide. Patients with an unmethylated MGMT promoter will be offered a study treatment with radiochemotherapy with enzastaurin. The outline of this study will be presented.