utility of these treatments to improve patient outcomes. The major challenges in the use of kinase inhibitors facing the neuro-oncology community are: (1) identiﬁcation of the optimal therapeutic target(s), (2) establishment of biomarkers of tumor sensitivity or resistance, and (3) optimization of signaling inhibitor combinations with either other inhibitors or cytotoxic agents for efﬁcacy and toxicity, as unusual adverse events such as neurotoxicity, hypertension and cardiac events can occur from those combinations. Vascular endothelial growth factor Vascular proliferation, or neoangiogenesis, is a histopatho- logical characteristic of MG.13,14 One attractive therapeutic target for many neoplasms is VEGF, the principal mediator of tumor angiogenesis. MG overexpresses VEGF, the levels of which correlate directly with tumor vascularity and grade, and inversely with prognosis.15–18 Tumor-associated endo- thelial cells express VEGFR2, creating a paracrine loop of angiogenic activation, indicating that VEGF and its receptors are important therapeutic targets.17,19 Bevacizumab (BV) is a humanized murine monoclonal antibody, binding VEGF-A20,21 and preventing interaction and activation of VEGF receptor tyrosine kinases VEGFR1 and VEGFR2.22 Given in combination with conventional chemotherapy, BV signiﬁcantly improves the survival of patients with metastatic colorectal and lung cancer23,24 and PFS of patients with breast cancer.25 BV with irinotecan has been approved by the US Food and Drug Administration (FDA) for colorectal cancer, as a ﬁrst line treatment for non-small cell lung cancer in combination with carboplatin and paclitaxel, and has obtained accelerated approval for metastatic HER2-negative breast cancer patients in combination with paclitaxel. Encouraging radiographic responses and PFS have been observed in MG exposed to BV (Avastin, Genentech, CA, USA) when used in combina- tion with irinotecan.26 In the ﬁrst phase II trial published, a radiographic response rate of 63% was observed (1 complete response [CR] and 19 partial responses [PRs]). In addition, a 6-month PFS of 32% was obtained in GBM patients. Due to the encouraging radiographic response rate observed, the initial trial was expanded to include a total of 68 patients with recurrent MG. In the total group of 68 patients, 35 patients had a pathological diagnosis of GBM while 33 had anaplastic glioma. Among all 35 recurrent GBM patients, the 6-month PFS was 46% (95% CI, 32%–66%) and the 6-month OS was 77% (95% CI, 64%–92%). Twenty of the 35 patients (57%; 95% CI, 39%–74%) had at least a PR. One patient developed a CNS hemorrhage and 4 patients developed thromboembolic Biologics:Targets & Therapy 2009:3 Malignant gliomas complications (deep venous thrombosis and/or pulmonary emboli).27 Similarly, among 33 recurrent anaplastic glioma patients, the 6-month PFS was 55% (95% CI, 36%–70%) and the 6-month OS was 79% (95% CI, 61%–89%). Twenty patients (61%) had at least a PR. Signiﬁcant adverse events were infrequent and included one patient with symptomatic CNS hemorrhage and one patient who developed thrombotic thrombocytopenic purpura (TTP). The patient with CNS hemorrhage required hospitalization and high-dose dexa- methasone, but made a full recovery following rehabilitative therapy. The patient who developed TTP remains on perito- neal dialysis without sign of disease progression.28 The preliminary results of a phase II, randomized, multi- center, non-comparative clinical trial of BV alone or in com- bination with irinotecan for GBM patients at ﬁrst or second recurrence have been published.29 Eighty-ﬁve patients were randomized to the BV alone group and 82 to the combination of BV plus irinotecan group. Patients in the BV alone group were allowed to receive the combination of BV and irino- tecan at the time of disease progression at the discretion of the investigator. Median OS were comparable at 9.2 months (95% CI, 8.2–10.7 months) for the BV alone group and 8.7 months (95% CI, 7.8–10.9 months) for the combination group. However, the 6-month PFS was higher in the com- bination group (50.3%; 95% CI, 36.8%–63.9%) than in the BV-alone group (42.6%; 95% CI, 29.6%–55.5%). Grade 3 and higher toxicities were higher in the combination group, 65.8% vs 46.4% for the BV alone group, but grade 5 adverse events were more frequent in the BV-alone group (2.4% vs 1.3% for the combination group).29 The unprecedented increase in PFS and response rate observed in MG patients when treated with the combination of BV and irinotecan has stimulated research with BV as well as other VEGF-directed or antiangiogenic therapies. Ongoing studies with agents more commonly used in MG patients are evaluating alternative BV-based regimens for recurrent MG patients. Two separate single-group studies combining BV with protracted, metronomic dosing sched- ules of either TMZ or etoposide are underway, as well as a study combining bortezomib, the ﬁrst proteasome inhibitor, and BV. Preliminary results on these studies have not yet been published. The Radiation Therapy Oncology Group (RTOG) is randomizing recurrent GBM patients to receive BV with either protracted TMZ (75 mg/m2/day for 21 days each month) or irinotecan every 2 weeks. An additional study combining BV plus daily erlotinib is also underway. Potentiation of RT by the inhibition of VEGFR signaling in GBM models has been demonstrated in preliminary 17