Desjardins et al in vitro and in vivo models of malignant gliomas, possibly by blocking the activated PI3K/AKT induced by the mTOR inhibition.70 Protein kinase C High dose tamoxifen has been shown to inhibit protein kinase C (PKC), a serine/threonine kinase that regulates cell proliferation, invasion and angiogenesis, and to have anti-tumor activity in glioma xenografts.71 However, tamoxifen mixed results have been reported in clinical trials.72–78 Enzastaurin (LY317615; Eli-Lilly, IN, USA), an oral serine/threonine kinase inhibitor targeting PKC and AKT pathways, induces tumor cell apoptosis and suppresses proliferation and angiogenesis.79 A response rate of 29% was reported in a phase II trial of recurrent MG.80 Unfortu- nately, a multi-centered phase III trial of enzastaurin versus lomustine in patients with recurrent GBM was discontinued at the interim analysis due to lack of beneﬁt over the control group.81 Patients were randomized 2:1 to receive 6-week cycles of 500 mg of enzastaurin daily (125-mg loading dose day 1) or lomustine (100–130 mg/m2 on day 1). Enroll- ment was terminated at 266 patients after a planned interim analysis for futility. Median PFS (HR = 1.28 [0.97, 1.70]), OS (HR = 1.2 [0.88, 1.65]) and a 6-month PFS rate were not different between groups. Four patients discontinued enzastaurin due to drug-related serious adverse events (AE) (erysipelas, aortic thrombosis, cerebral hemorrhage, and convulsion). Eleven (7%) patients on enzastaurin died (4 due to AEs, 1 of which was drug-related). In the lomustine group, all four (5%) deaths were disease-related. Grade 3–4 hematological toxicities were signiﬁcantly higher for lomustine (p 0.001). No anemia, neutropenia, or leuko- penia occurred on enzastaurin, and only 1 patient had throm- bocytopenia vs 21 on lomustine. There were no signiﬁcant differences in grade 3–4 non-hematological toxicities between arms. The authors concluded that enzastaurin had a better toxicity proﬁle but was not superior to lomustine in patients with recurrent GBM.81 Integrins Integrins are cell adhesion molecules important in glioma cell invasion, migration, proliferation, survival, and angiogenesis by their interactions with multiple extracel- lular ligands, including vitronectin, ﬁbronectin, laminin, ﬁbroblast-growth factor, MMP-2, thrombospondin, ﬁbrin, and ﬁbrinogen.82–85 Cilengitide (EMD121974; EMD Phar- maceuticals, NC, USA), an intravenous inhibitor of αvβ3 and αvβ5 integrin receptors demonstrated the absence of 20 dose-limiting toxicity and a radiographic response rate of 10% in a phase I trial for MG.86 A phase II study of single-agent cilengitide randomized recurrent GBM patients to either an intermediate–low dose (500 mg) or an inter- mediate–high dose (2000 mg). No reproducible toxicities were observed in either group, and outcome trended more favorably among patients treated at the higher dose level, including a 6-month PFS of 15% vs 9.7% and a 12-month OS of 37.5% (95% CI 22.7%–54.2%) vs 22% (95% CI 10.6–37.6).87 Radiographic response occurred in both groups but a higher rate was observed among patients treated at 2000 mg (12.5%) compared to patients treated with 500 mg (4.8%). Also, preliminary results of a multi-center trial of cilengitide (500 mg twice weekly) in addition to RT and TMZ for patients with newly diagnosed GBM patients recently reported a 6-month PFS of 69% (95% CI 55%–83%) and a 12-month OS of 67% (95% CI 42%–92%). Also, no added toxicity was observed when cilengitide was added to RT and TMZ.88 Additional studies with cilengitide are ongo- ing or planned including a trial evaluating the intratumoral pharmacodynamics and pharmacokinetics of cilengitide in recurrent GBM patients treated with cilengitide prior to a planned debulking procedure by the NABTC, a trial evaluat- ing cilengitide dosed at 2000 mg twice weekly in combina- tion with RT and TMZ by the New Approaches to Brain Tumor Therapy (NABTT) and a multi-center, randomized phase III trial for newly diagnosed GBM patients. Combination therapies To date, the presence of multiple parallel and/or compensa- tory pathways and MG heterogeneity likely contributes to the limited activity observed with single agent therapy using molecularly targeted agents in MG patients. Multiple strate- gies are being evaluated to help overcome these factors. One such strategy is the use of tyrosine kinase inhibitors with multiple targets and a second strategy is to combine them with cytotoxic agents. Tyrosine kinase inhibitors with multiple targets AEE788 (Novartis), a dual inhibitor of EGFR and VEGFR-2, has shown preclinical efﬁcacy in murine models of glioblastoma.89 Vandetanib (ZD6474, Zactima®; Astra- Zeneca), another dual inhibitor of EGFR/VEGFR-2, also demonstrated survival beneﬁts in a murine model of intracra- nial glioma xenografts.90 Clinical trials of vandetanib in MG are ongoing. Sunitinib malate (Sutent®, SU11248; Pﬁzer), an inhibitor of VEGFR-2, PDGFR, c-KIT and FMS-like Biologics:Targets & Therapy 2009:3