Desjardins et al orally daily, days 1 through 5, every 28 days) and the control group received RT alone. Patients in the RT alone group were allowed to receive TMZ at the time of disease progression. A median survival of 14.6 months was observed in patients treated with concurrent RT and TMZ followed by 6 monthly cycles of TMZ, compared to 12.1 months for patients treated with RT alone. Also, the 2-year survival rate improved from 10.4% for RT alone to 26.5% in the RT-TMZ group.8 They observed no grade 3 or 4 hematologic toxicities in the RT alone group. In the RT-TMZ group, 12 patients (4%) expe- rienced grade 3 or 4 neutropenia and 9 patients (3%) had grade 3 or 4 thrombocytopenia. During the adjuvant TMZ therapy of the RT-TMZ group, 14% of patients had any grade 3 or 4 hematologic toxicities (4% grade 3 or 4 neutropenia, 11% grade 3 or 4 thrombocytopenia). During the RT period, severe infections occurred in 6 patients (2%) in the RT alone group and in nine patients (3%) in the RT-TMZ group, during adjuvant TMZ therapy, 12 patients (5%) experi- enced severe infections. Other common non-hematologic toxicities included: moderate to severe fatigue (26% RT alone group, 33% RT-TMZ group), thromboembolic events (6% RT alone group, 4% RT-TMZ), pneumonia (2% RT alone group, 1% RT-TMZ group), and opportunistic infec- tions (one patient in each group). Finally, 2 patients in the RT-TMZ group died of cerebral hemorrhage in the absence of a coagulation disorder or thrombocytopenia. Gene methylation is an important cellular mechanism of transcription suppression. O6-methylguanine-DNA- methyltransferase (MGMT) is a critical DNA repair protein, which removes chloroethylation, or methylation damage from the O6 position of DNA guanines, protecting the tumor cells against alkylating and methylating chemotherapeutic agents.9 The presence of MGMT gene methylation predicts for lack of MGMT expression and subsequent TMZ sen- sitivity, whereas the absence of MGMT gene methylation (unmethylated MGMT) predicts MGMT expression and potential TMZ resistance. Analyses of tumor specimens from patients treated on the Stupp trial8 were performed to determine the methylation status of MGMT and its correlation with survival. Patients with MGMT gene meth- ylation who received RT and TMZ achieved a median PFS of 10.3 months and a 2-year survival rate of 46%, compared to 5.9 months median PFS and 22.7% 2-year survival rate for the patients having MGMT gene methylation but treated with RT alone. In comparison, patients with unmethylated MGMT achieved a median PFS of 5.3 months and a 2-year survival rate of 14% for the RT-TMZ group and 4.4 months and 2%, respectively for the group receiving only RT.10 16 It was concluded that patients with newly diagnosed GBM and MGMT gene methylation beneﬁted the most from the addition of TMZ to RT.10 A possible approach to improve the survival of patients with unmethylated MGMT is molecules that can reverse the process, such as O6-benzylguanine (O6-BG), an O6-alkylguanine-DNA alkyltransferase inhibitor. Phase I studies of O6-BG with BCNU and TMZ have been limited by hematologic toxicities preventing therapeutic dose escalation of the chemotherapy.11,12 Even though the addition of TMZ to RT provides an important step forward in the overall treatment of this disease and nitrosoureas remain an option, more effective therapies are necessary. Several innovative treatment strategies, includ- ing targeted therapeutics as well as locally administered agents, are being studied. Targeted therapies The recent success of small-molecule inhibitors of signal transduction pathways in other cancers has propelled rapid development of similar therapies in the treatment of patients with MG. Cellular processes contributing to normal homeostasis, once disrupted, can contribute to malignancy and this by the presence of common molecular alterations in the signal transduction pathways, a communication network of regulatory molecules within the cell. Several growth factors, hormones, and cytokines regulate these cellular processes. Epidermal growth factor (EGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), hepato- cyte growth factor/scatter factor (HGF/SF), and insulin-like growth factor (IGF) are some of the relevant growth factor pathways in gliomas. Tyrosine kinases are associated with the receptors for these pathways. After ligand binding, the recep- tors undergo dimerization that permits transphosphorylation, in which the kinase domain of one receptor phosphorylates one or more intracellular tyrosine residues on the second receptor. Phosphotyrosine residues recruit adaptor proteins, activating downstream effector molecules that initiate signaling cascades to regulate gene transcription in the nucleus. MG are known to present overexpression or mutations of receptors and intracel- lular downstream effectors, leading to activation of signaling pathways, resulting in uncontrolled cellular proliferation, survival, and invasion. Several approaches are available to inhibit signaling pathways, from the inhibition of upstream growth factor ligands and their receptors, to the inhibition of downstream intracellular effectors. Speciﬁc inhibitors of these targets have shown promise in preclinical and clinical trials; however, signiﬁcant work remains to maximize the Biologics:Targets & Therapy 2009:3