that inhibits EGFR-speciﬁc tyrosine phosphorylation and has demonstrated antitumor efﬁcacy similar to that of geﬁnitib in preclinical studies. A phase I trial of erlotinib as monotherapy or in combination to TMZ demonstrated a response rate of 14% and a 6-month PFS of 11%.48 Subsequent phase II trials of erlotinib have demonstrated response rates of 6% to 25% with minimal effect on the progression rate and survival.49,50 A beneﬁt in stratifying patients for EGFR targeted therapies has been suggested by two recent studies, demonstrating that co-expression of normal PTEN and mutant EGFRvIII,51 and combined low levels of AKT and overexpression of EGFR,52 predict radiographic responses in MG patients treated with erlotinib or geﬁtinib. Platelet derived growth factor Imatinib mesylate (Gleevec®; Novartis, NJ, USA), a kinase inhibitor of PDGFR, c-Kit and bcr-abl, has limited anti-glioma activity when administered as monotherapy53 and in combination with RT.54 Speciﬁcally, the response rate was less than 6% and the 6-month PFS was less than 16% in recurrent MG patients.55 In contrast, Dresemann demonstrated encouraging anti-glioma activity when imatinib was combined with hydroxyurea.56 Two subsequent phase II studies con- ﬁrmed this observation. A response rate of 9% and a 6-month PFS of 27% were observed in recurrent GBM patients57 and a response rate of 10% and a 6-month PFS of 24% were observed in recurrent AA/AO patients.58 A phase II, open-label, multi-centre, single-group study evaluating the efﬁcacy of ima- tinib plus hydroxyurea in patients with progressive GBM that are receiving enzyme-inducing anticonvulsant drugs (EIACDs) has completed enrollment and analysis is underway. RAF-MEK-ERK The RAF-MEK-ERK signal transduction pathway, an important mediator of dysregulated glioma cell proliferation and angiogenesis, also offers potential therapeutic targets. In the cytoplasmic part of cell membrane, small guanine triphosphate (GTP)-binding proteins, encoded by the RAS superfamily of genes, regulate numerous cellular functions including proliferation, differentiation, cytoskeletal organi- zation, protein trafﬁcking, and the secretion of angiogenic factors. Mutation or ampliﬁcation of upstream growth factor receptors in gliomas often result in increased RAS activity.59 Farnesylation is the rate-limiting step in RAS maturation;60 therefore, several farnesyltransferase inhibitors (FTI) have undergone clinical evaluation as RAS targeted therapy. However, FTI activity may not be speciﬁc to RAS, as many other oncoproteins also undergo farnesylation. Biologics:Targets & Therapy 2009:3 Malignant gliomas Tipifarnib (Zarnestra® R115777; Johnson and Johnson, NJ, USA) and lonafarnib (Sarasar®, SCH66336; Schering-Plough, NJ, USA) may inactivate RAS by inhibiting farnesyltransferase. In a phase I/II study, tipifarnib demonstrated a 6-month PFS of 9% in recurrent AA/AO and of 12% in recurrent GBM.61 Lonafarnib was evaluated in a phase I trial in combination with TMZ for patients with prior TMZ failure. A response rate of 27% and a 6-month PFS of 33% was observed.62 Additional molecules inhibiting components of the RAF-MEK-ERK path- way are under investigation and include AAL881 (Novartis)63 and sorafenib (Nexavar; Bayer, CT, USA). PI3K/AKT/mTOR PI3K, a serine/threonine kinase activated by several receptor tyrosine kinases, active RAS, or integrins, regulates several malignant phenotypes including apoptosis, cell growth, and proliferation. Poor prognosis of MG patients is associ- ated with the activation of PI3K pathways.64 A constitutive activation of PI3K pathways is seen with PTEN loss, a common genetic feature in GBM. Activated PI3K phosphorylates several downstream effectors including AKT, another serine/threonine kinase regulating apoptosis, cell growth, and proliferation. Inhibitors of PI3K and AKT have undergone preclinical evaluation with encouraging results.65 Perifosine (Keryx Biopharmaceuticals, New York, NY), an oral AKT inhibitor, administered as an oral loading dose of 600 mg on day one followed by 100 mg nightly there- after is undergoing clinical evaluation in MG. Preliminary results showed a response rate of 15%, but updated data are to come.66 mTOR, a serine/threonine kinase downstream from AKT, is activated not only by AKT but also by RAS path- ways. Rapamycin (sirolimus; Wyeth, Madison, NJ) and its synthesized analogs, temsirolimus (CCI-779; Wyeth), everolimus (RAD001; Novartis), and AP23573 (Ariad Pharmaceuticals, Cambridge, MA, USA) have been evalu- ated in clinical trials of MG. Two recent phase II studies of temsirolimus in recurrent GBMs by the NABTC and the NCCTG have demonstrated modest efﬁcacy.67,68 A radio- graphic response rate of 5% and 36%, and a 6-month PFS of 2.5% and 7.8%, were observed in the NABTC and NCCTG trials, respectively.67,68 The NCCTG trial demonstrated that a predictor of radiographic response was a high level of p70s6K phosphorylation in tumor at baseline.68 A stimulation of the kinase activity of AKT, the immediate upstream effector of mTOR, has been demonstrated following the inhibition of mTOR in preclinical studies.69 PI-103, a novel inhibitor of both PI3K and mTOR, has shown promising activity in both 19