Expert Reviews - Expert Review of Anticancer Therapy = - 9(1):7

New = developments=20 in targeted molecular therapies for=20 glioblastoma

Sections:

INTRODUCTION	Top of pageINTRODUCTION = <<References

Glioblastoma multiforme is the most = common type=20 of malignant primary brain tumor in adults. Each year = it is=20 estimated that there are over 10,000 cases of the = tumor=20 diagnosed in the USA [1,2]. = Despite=20 optimal treatment with surgery and radiation therapy = with=20 concomitant and adjuvant temozolomide, median survival = is=20 usually less than 15 months [3]. Until = recently,=20 there was no effective therapy for these tumors when = they=20 recurred, with a 6-month progression-free survival = (PFS6) of=20 only 8=E2=80=9315% [4,5].

In recent years, there has been significant = progress in=20 understanding the molecular pathogenesis of = glioblastomas [6,7]. = This has=20 resulted in increasing interest in the therapeutic = potential=20 of targeted molecular therapies [8,9].=20 Unfortunately, the results with single agents = inhibiting=20 receptor tyrosine kinases, such as the EGF receptor = (EGFR) and=20 PDGF receptor, or signal transduction pathways = components,=20 such as farnesyltransferase or mTOR, have been = disappointing=20 [8,9]. = Response=20 rates have, generally, been less than 10=E2=80=9315% = with no=20 prolongation of PFS6. Reasons for these poor results = include=20 coactivation of multiple tyrosine kinases [10] and = redundant=20 signaling pathways, limiting the activity of single = agents. In=20 addition, penetration of many agents across the = blood=E2=80=93brain=20 barrier is poor and compounded by active efflux of = drugs via=20 P-glycoprotein and other pumps. Attempts to define = subsets of=20 patients that respond to specific agents have also met = with=20 limited success. Initial studies suggested that EGFR=20 inhibitors appear to be more effective in tumors with = EGFRvIII=20 mutations and intact phosphatase and tensin homolog = deleted on=20 chromosome 10 [11], while = tumors=20 with increased activity of the PI3K/Akt pathway, as = determined=20 by increased phospho-Akt, generally do not respond [12]. = However, recent=20 studies have failed to validate the utility of = EGFRvIII=20 mutations and intact PTEN as markers of responsiveness = to EGFR=20 inhibitors [13].

In an attempt to improve the effectiveness of = targeted=20 molecular therapies, there is growing interest in = using=20 multitargeted agents that inhibit several kinases,=20 combinations of agents inhibiting complementary = targets, such=20 as EGFR and mTOR, and combinations of targeted agents = with=20 radiotherapy and chemotherapy. The utility of these = approaches=20 remains to be determined, but preliminary results = suggest that=20 many combinations of targeted agents are poorly = tolerated. For=20 example, the North American Brain Tumor Consortium = recently=20 completed accrual to a Phase I/II trial of erlotinib = (EGFR=20 inhibitor) and temsirolimus (mTOR inhibitor) [14]. The = maximum=20 tolerated dose of temsirolimus when used in = combination was=20 only 15 mg once weekly compared with the single-agent = dose of=20 170 mg once weekly. This large reduction potentially = results=20 in administration of subtherapeutic doses of the drug. = Nonetheless, combination therapy represents an = attractive=20 therapeutic strategy and other agents may potentially = be=20 better tolerated. The recent availability of more = potent and=20 often irreversible inhibitors with improved brain = penetration,=20 for example, EGFR inhibitors (e.g., BIBW2992), agents = that=20 inhibit critical targets (e.g., PI3K, Akt and c-Met), = agents=20 that inhibit multiple targets (e.g., heat-shock = protein 90 and=20 NF-=CE=BAB) and agents that promote apoptosis or = inhibit DNA repair=20 enzymes (e.g., = O6-methylguanine-DNA-methyltransferase=20 or poly-[ADP-ribose]-polymerase) has led to renewed = interest=20 in targeted molecular therapies. In addition, given = the=20 increasing importance of stem cells in gliomagenesis = [15] and = mediating=20 resistance to therapy [16], there = is also=20 significant interest in molecular therapies targeting = stem=20 cell pathways, such as notch and sonic hedgehog. The = lessons=20 learned from the previous generation of trials has led = to=20 improved study design [17]. Many = trials now=20 incorporate a pharmacodynamic component, in which = patients=20 requiring re-operation are pretreated with the = targeted agent.=20 Examination of the tumor specimens provides an = indication of=20 the drug=E2=80=99s ability to penetrate into the tumor = across the=20 blood=E2=80=93brain barrier and inhibit putative = targets in=20 vivo [17]. = Ideally,=20 clinical trials would include an enriched population = of=20 patients whose tumor expresses that molecular target = of=20 interest. However, this approach remains a challenge = given=20 that there is a lack of validated molecular markers = predicting=20 response. There is also increasing interest in novel = trial=20 designs incorporating strategies, such as sequential = accrual,=20 factorial design or =E2=80=98pick the winner=E2=80=99 = designs in an attempt to=20 test multiple combinations efficiently and eliminate=20 ineffective regimens more rapidly.

In contrast to the relatively disappointing results = with=20 other targeted molecular therapies, there has been = real=20 progress with agents that inhibit angiogenesis. Over = three=20 decades ago, Judah Folkman proposed the hypothesis = that=20 inhibition of angiogenesis may, potentially, be an = effective=20 treatment for cancers [18]. = Glioblastomas=20 are among the most vascularized tumors in the body and = represent a particularly attractive target for this=20 therapeutic strategy. These tumors secrete a variety = of=20 angiogenic factors, such as VEGF, PDGF, basic FGF = (bFGF)/FGF2=20 and HGF/scatter factor, which contribute to = neovascularization=20 [19]. In = addition,=20 VEGF is an important cause of the increased vascular=20 permeability and peritumoral edema that contributes=20 significantly to the morbidity associated with these = tumors [19].

Studies with early antiangiogenic agents, such as=20 thalidomide, produced only minimal benefits, with = response=20 rates of less than 10% and no prolongation of PFS. = However,=20 the recent availability of more-potent antiangiogenic = agents,=20 especially those targeting VEGF and its receptors = (VEGFR), has=20 led to important progress in the treatment of = glioblastomas [19=E2=80=9322].=20 Bevacizumab (Avastin^=C2=AE) is a humanized = monoclonal=20 antibody that binds VEGF, preventing it from = activating its=20 receptors, especially VEGFR2 and, therefore, = abrogating=20 subsequent biologic effects. Bevacizumab has been = evaluated=20 alone and in combination with various chemotherapeutic = agents=20 in recurrent glioblastomas with encouraging results. = In one=20 Phase II study, the combination of bevacizumab and = irinotecan=20 produced a response rate of 57% and a PFS6 of 46% in = recurrent=20 glioblastomas [23]. By = comparison,=20 ineffective therapies provide response rates of less = than 10%=20 and PFS6 of 15% in glioblastomas [4]. Although = the high=20 response rates may be partly the result of reduced = vascular=20 permeability and contrast enhancement as a result of = VEGF=20 inhibition, the improvement in PFS6 suggests that = there is=20 also a real anti-tumor effect. The regimen was = generally well=20 tolerated, with a low incidence of intracerebral = hemorrhage.=20 These preliminary findings have been confirmed by a = large=20 multicenter randomized Phase II study of 167 patients = with=20 recurrent glioblastomas who were treated with = bevacizumab=20 alone or in combination with irinotecan [21]. = Patients=20 receiving bevacizumab alone had a response rate of = 28.2% and a=20 PFS6 of 42.6%, while patients receiving bevacizumab in = combination with irinotecan had a response rate of = 37.8% and a=20 PFS6 of 50.3% [21]. = However, median=20 survival was similar between the two groups (9.2 = months for=20 bevacizumab alone and 8.7 months for the combination), = making=20 it unclear whether the use of irinotecan provides any=20 additional benefit. Patients treated with bevacizumab = also=20 experienced a significant reduction in peritumoral = edema and=20 the need for corticosteroids, significantly improving = the=20 quality of life of patients. This study, again, = confirmed that=20 bevacizumab was well tolerated, with a low incidence = of=20 intracranial hemorrhage. As a result of these studies, = bevacizumab, often combined with irinotecan, is = increasingly=20 used for the treatment of patients with recurrent=20 glioblastomas.

Aflibercept (VEGF-Trap) is a soluble hybrid = receptor,=20 composed of portions of VEGFR-1 and -2 fused to an=20 immunoglobulin G1 Fc domain. As with bevacizumab, it = is=20 designed to deplete circulating VEGF, but has = significantly=20 greater affinity for VEGF than bevacizumab itself. A = Phase II=20 study conducted by the North American Brain Tumor = Consortium=20 was recently completed with response rates similar to = those=20 obtained with bevacizumab [24].

There are also encouraging results with inhibitors = of=20 VEGFRs. In a Phase II trial study of a potent = pan-VEGFR=20 inhibitor, cediranib (AZD2171; Recentin=E2=84=A2), in = patients with=20 recurrent glioblastomas, response rates in excess of = 50% were=20 observed and the PFS6 was increased to approximately = 25% [25]. At the = time of=20 tumor recurrence, serum levels of bFGF/FGF2, = SDF1=CE=B1 and=20 circulating endothleial cells were increased, together = with=20 Tie2, suggesting that these may be contributing to = resistance=20 to VEGFR inhibition. Studies with other inhibitors of = VEGFR,=20 such as vandetanib (ZD6474; Zactima=E2=84=A2), = sorafenib=20 (Nexavar^=C2=AE), sunitinib = (Sutent^=C2=AE),=20 pazopanib (GW786034), vatalanib (PTK787) and CT322, in = glioblastomas are in progress.

In comparison to drugs targeting VEGF or VEGFR, = agents=20 inhibiting other angiogenic pathways have produced = less=20 success. Drugs that inhibit PDGF receptors, such as = imatinib=20 mesylate (Gleevec^=C2=AE), were ineffective, = due partly=20 to its poor penetration across the blood=E2=80=93brain = barrier [26,27].=20 Cilengitide, a drug that inhibits = =CE=B1_v=CE=B2₃=20 and =CE=B1_v=CE=B2₅ integrins has = shown modest=20 activity in glioblastomas [28], and = studies=20 combining it with other agents are in progress [8].

Since antiangiogenic agents can potentially have=20 synergistic effects with radiation therapy, there is=20 significant interest in combining these agents with = radiation=20 therapy [29]. Two = Phase III=20 trials evaluating the benefits of adding bevacizumab = to=20 radiation therapy and temozolomide for the treatment = of newly=20 diagnosed glioblastomas will begin in the near future. = These=20 studies will help determine the safety of bevacizumab = in newly=20 diagnosed glioblastomas and whether it is more = effective as=20 first-line treatment or at recurrence. Given the = vascular=20 niche of normal neural stem cells and its potential = disruption=20 with antiangiogenic therapy, it will be important to = determine=20 if the addition of agents such as bevacizumab to = radiation=20 therapy increases the risk of delayed neurocognitive=20 impairment.

After over two decades of minimal progress in the = treatment=20 of recurrent glioblastomas, antiangiogenic therapies, = such as=20 bevacizumab, represent an important but limited = advance. In=20 addition, by reducing peritumoral edema, these agents=20 frequently allow patients to decrease or eliminate = their need=20 for corticosteroids, improving their quality of life. = The risk=20 of hemorrhage with these agents is modest but they are = associated with other complications, such as an = increased risk=20 of venous thromboembolism, impaired wound healing, = proteinuria=20 and hypertension. These agents are also very = expensive, and=20 important issues regarding their economics remain to = be=20 resolved.

As experience with antiangiogenic = agents=20 accumulates, it is clear that the benefits are only = transient,=20 and most tumors eventually progress after a number of = months.=20 In a subset of patients, these tumors recur, not as = enhancing=20 masses, but with a more infiltrative phenotype = resembling=20 gliomatosis [30]. This = raises the=20 possibility that by inhibiting angiogenesis, anti-VEGF = and=20 anti-VEGFR agents force tumor cells to co-opt and grow = along=20 existing blood vessels, changing their natural history = [31,32].=20 Unfortunately, most conventional therapies are = generally=20 ineffective for patients who progress on bevacizumab = and=20 subsequent survival is often limited. As a result, it = is=20 unclear whether the improvements in PFS produced by = these=20 agents translate into a significant increase in = overall=20 survival. In order to improve on the advances made = with=20 bevacizumab and other anti-VEGF/VEGFR agents, it will = be=20 critical to identify the mechanisms that determine = intrinsic=20 resistance of subsets of glioblastomas to these = agents, as=20 well as the mechanisms that develop during therapy = that allow=20 the tumor to eventually progress after an initial = response.=20 These mechanisms of =E2=80=98evasive = resistance=E2=80=99 are thought to=20 include upregulation of alternative proangiogenic = signals,=20 such as FGF-1 and -2, SDF1=CE=B1, ephrins and = angiopoietins,=20 leading to revascularization, protection of the tumor=20 vasculature either by recruiting proangiogenic = inflammatory=20 cells or by increasing protective pericyte coverage, = as well=20 as co-option of normal vasculature and invasion into=20 surrounding tissue [33]. = Combining agents=20 targeting VEGF with inhibitors of FGF, SDF1=CE=B1, = ephrins or Tie2=20 may, potentially, lead to improved tumor control. = Given the=20 increasing importance of invasion as a mechanism of=20 resistance, combining antiangiogenic agents with drugs = that=20 inhibit invasion also holds great promise [34]. These = approaches=20 will hopefully allow us to build on the recent = progress that=20 has occurred with the introduction of potent = antiangiogenic=20 agents, such as bevacizumab.

Financial &=20 competing interests disclosure=20

PY Wen has received research support from = Genentech,=20 AstraZeneca, Exelixis, Schering Plough, Amgen and = Novartis.=20 The author has no other relevant affiliations or = financial=20 involvement with any organization or entity with a = financial=20 interest in or financial conflict with the subject = matter or=20 materials discussed in the manuscript apart from those = disclosed.

No writing assistance was utilized = in the=20 production of this manuscript.

References	Top of pageINTRODUCTIONReferences = <<

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Affiliations

Patrick Y Wen

Center For Neuro-Oncology, = Dana=20 Farber/Brigham and Women=E2=80=99s Cancer Center, = SW430D, 44 Binney=20 Street, Boston, MA 02115, USA; and, Division of=20 Neuro-Oncology, Department of Neurology, Brigham and = Women=E2=80=99s=20 Hospital, Boston, MA 02115, USA. pwen@partners.org=20

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