tyrosine kinase (FLT)-3, has activity against a subcutaneous malignant glioma xenograft.91 A phase II study of sunitinib malate in MG is under development. Targeted therapies combined with cytotoxic agents Promising activity has been observed with imatinib mesylate in combination with hydroxyurea (see above). Also, a phase I trial of imatinib mesylate with temozolomide is underway.92 Geﬁtinib93 and erlotinib48 have been evaluated in combination with TMZ. In an effort to enhance the sensitivity of glioma cells to RT, multiple agents are evaluated in combination with RT including geﬁtinib and erlotinib with or without TMZ,94 imatinib mesylate, tipifarnib,95 mTOR inhibitors,96 vandetanib and BV. Locoregional therapies Locoregional therapies are promising approaches due to their ability to circumvent the BBB, to minimize systemic toxicity, and to concentrate therapy at the primary tumor site, which is well-recognized to be the site of tumor recurrence in most MG patients.97,98 Gliadel®, a controlled-release, biodegradable polymer releasing carmustine (BCNU), was the ﬁrst approved locoregional therapy for MG.99 Double-blind, randomized, placebo-controlled studies using Gliadel implantation in surgically resectable cases provided an 8-week survival beneﬁt and a 2.3-month survival beneﬁt in recurrent GBM and newly diagnosed MG, respectively.100,101 Delivery of high dose radiation to the tumor bed via stereotactic radiosurgery (SRS) is another locoregional strategy. However, among newly diagnosed GBM patients, no improvement in survival was seen when SRS was added to conventional RT plus BCNU chemotherapy.102 The role of brachytherapy with 125I-beads implanted into the resec- tion cavity is limited by a high rate of radiation necrosis requiring surgical debulking.103–105 GliaSite®, a commercially available product consisting of an aqueous solution of organically bound 125I (Iotrex™ [sodium 3-((125)I)-iodo-4- hydroxybenzene-sulfonate]; Cytyc Corp, Marlborough, MA) that delivers low-dose-rate radiation via a temporarily inﬂated balloon catheter following resection, is undergoing evaluation for newly diagnosed and recurrent MG. Modest results have been observed thus far with a 1 year survival rate of 31.1% for patient with recurrent WHO grade III and IV.106 Encourag- ing survival beneﬁts have been noted in single group studies evaluating the administration of radiolabeled antitenascin monoclonal antibodies into the resection cavity of newly diagnosed and recurrent MG patients, with a low rate of radia- Biologics:Targets & Therapy 2009:3 Malignant gliomas tion necrosis requiring surgical debulking.107,108 In a phase II study evaluating the administration of 100 mCi of 131I-m81C6 followed by chemotherapy to recurrent MG patients, a median OS for patients with GBM and WHO grade III tumors of 64 and 99 weeks respectively was observed.109 A multi-center phase III randomized study of 131I-labeled anti-tenascin murine monoclonal antibody (Neuradiab; Bradmer Phar- maceuticals, Inc, Toronto, ON) in combination with RT and TMZ versus RT and TMZ in patients with newly diagnosed GBM has just been initiated. Convection enhanced delivery (CED) involves the gradual infusion of a therapeutic molecule over 3 to 5 days via micro- infusion catheters strategically placed in the peritumoral region. The consistent positive infusion pressure gradient achieved by CED offers the possibility to overcome the increased intratumoral interstitial pressure that limits the intracranial delivery of systemically administered therapeu- tics for MG patients.110 In this manner, CED can potentially deliver therapeutic agents homogeneously into clinically signiﬁcant volumes of distribution.111 Convection enhanced delivery of IL-13 conjugated with pseudomonas exotoxin (cintredekin besudotox, IL13-PE38QQR; NeoPharm, IL, USA) had shown encouraging results in phase I/II study for MG.112 Unfortunately, a recently completed phase III trial with this agent administered by CED failed to achieve a survival beneﬁt compared to control patients randomized to receive carmustine wafers (Gliadel®).113 The evaluation of additional molecules or toxins via CED is underway. Conclusions and future directions Given the dismal prognosis associated with traditional cytotoxic agents for MG patients, there is an urgent need for more effective therapies. Thanks to intensive labora- tory research conducted over the past several years, many molecular genetic and signal transduction pathway targets have been identiﬁed that are now being evaluated thera- peutically. The identiﬁcation of tumor phenotypes, MGMT gene methylation status, EGFRvIII, PTEN, and so on, have already demonstrated their signiﬁcance (improved prognosis of patients with MGMT gene methylation treated with TMZ,10 better radiographic response to erlotinib for patients demonstrating co-expression of normal PTEN and mutant EGFRvIII51). However, additional information and understanding is necessary, as the inhibition of one pathway is known to induce the activation of a second pathway. In addition, novel locoregional treatments as well as strategies to improve regional delivery are being evaluated. Given the challenges posed by the heterogeneity within and across 21