Adjusting for age and KPS, no other biomarker was associated with survival outcome. Correlation of relevant biomarkers with OS may be useful in future trials. Keywords: adjuvant therapy, enzastaurin, chloroxine glioblastoma multiforme, radiation therapy, temozolomide. The standard of care for newly diagnosed glioblastoma multiforme or gliosarcoma includes surgical resection, followed by radiation Raf Inhibitors therapy with concurrent temozolomide, an alkylating agent, and by adjuvant temozolomide. In a definitive phase III trial, patients treated with the temozolomide plus RT regimen had significantly improved overall survival , compared with patients who received RT alone. However, the 2 year survival rate for patients treated with temozolomide plus RT was only 26.5%.
1 Therefore, additional therapeutic strategies are needed Molecular studies have identified numerous genetic alterations associated with initiation and progression of brain cancer that may serve as targets for molecular therapies to further improve patient survival.2,3 Enzastaurin is an example of a targeted agent that is a selective serine/threonine kinase inhibitor of protein Telaprevir structure kinase C . Enzastaurin disrupts the phosphotransferase activity of PKC isoforms via an interaction at the ATP binding site and displays selectivity in inhibiting the beta isoform.4 The PKC family of enzymes is essential to tumor growth, proliferation, and apoptosis.5,6 The beta isoform of PKC also lies in the signal cascade of vascular endothelial growth factor that is upregulated in GBM concomitant with overexpression of VEGF receptor; 7,8 inhibition of this pathway by enzastaurin blocks tumor angiogenesis and growth.
9 PKC activity is also thought to regulate AKT, a protein that has antiapoptotic effects and is involved in GBM proliferation.10 12 Thus, inhibition of the AKT pathway by enzastaurin may lead to decreased cell growth and increased cell death. Preclinical studies have shown the antiproliferative and antiangiogenic activity Calcitriol solubility of enzastaurin in tumor models, including glioma.9,13 Enzastaurin has also been shown to enhance the efficacy of RT by preventing unwanted proinvasive and angiogenic effects and to enhance temozolomide induced cell death in GBM cell lines.14 Clinical studies in healthy volunteers and patients with solid tumors show that enzastaurin is well tolerated at doses that achieved a biologically active serum concentration.
15 17 Results from a phase II study of patients with recurrent high grade gliomas demonstrated that enzastaurin was well tolerated, with possible antitumor activity, although not robust.18 In addition, we previously reported on a phase I trial of enzastaurin given with temozolomide plus RT that resolutions also showed that the combination was well tolerated, and the results of that study formed the basis for dosing schedules tested in the current study.19 On the basis of these promising data, we conducted a phase II study to determine the efficacy of enzastaurin in patients with newly diagnosed GBM or gliosarcoma who also received concomitant temozolomide and RT. Of note, the current study was developed and opened before the release of the results of a phase III study of enzastaurin, compared with lomustine, in the treatment of recurrent GBM; the phase III study reported that enzastaurin .