angiogenic inhibition in high-grade gliomas: past, present and future

10.1586/ERN.12.53 733ISSN 1473-7175© 2012 Expert Reviews Ltdwww.expert-reviews.com

Review

High-grade gliomas, which include glioblastoma (GBM; WHO Grade IV) and anaplastic glioma (AG; WHO Grade III), are the most common primary malignant brain tumors, accounting for 76% of all gliomas. GBM is more common in males, and incidence increases with increasing age [1]. These tumors are highly aggressive, and historically less than 5% of patients with GBM survive for more than 5 years post-diagnosis [1]. Despite treatment with the standard protocol using fractionated external beam radiotherapy with concomitant and adjuvant temozolo-mide after maximal tumor resection, survival remains dismal, with a median survival of only 14.6 months and only 10% 5-year survival [2,3]. For patients with AG, median survival is only 2–5 years [4–6]. At recurrence, only 21% of patients with GBM and 46% with AG survive for 6 months after temozolomide treatment [7,8]. At present, there is no standard treatment for tumor recurrence.

The role of VEGF in the pathobiology of GBM is well recognized and has been a major focus of treatment strategies for these tumors for several years [9]. Bevacizumab, the prototype antiangiogenic agent, has been approved for the treatment of metastatic colon carcinoma, non-squamous non-small-cell lung carcinoma and metastatic renal cell carcinoma [10]. Several stud-ies have investigated the benefits of bevacizumab and other antiangiogenic agents in patients with high-grade gliomas, both upfront and as salvage therapy. In 2009, bevacizumab was approved as a single agent in the treatment of progressive GBM [9,11]. Bevacizumab-based regimens are now widely used for recurrent high-grade glioma.

Despite the promising results of antiangiogenic therapy in high-grade gliomas, several issues require elucidation, including mechanisms of resistance to these agents, assessment of true anti-tumor response and predictive biomarkers. This study aims to review the past developments,

Jasmin Jo, David Schiff* and Benjamin PurowDepartment of Neurology, Division of Neuro-Oncology, University of Virginia, Charlottesville, VA 22908-0432, USA*Author for correspondence: Tel.: +1 434 982 4415 Fax: +1 434 982 4467 [email protected]

High-grade gliomas, especially glioblastoma (GBM), are among the most aggressive and vascularized tumors. Angiogenesis plays a significant role in tumor growth and survival, and thus offers a target for anticancer treatment. Bevacizumab, a humanized monoclonal antibody against VEGF, was approved by the US FDA as a single agent for the treatment of recurrent glioblastoma. Significant radiographic response and progression-free survival were seen with bevacizumab treatment. However, benefits to overall survival remain undetermined. Other antiangiogenic strategies targeting VEGF, VEGF receptor (VEGFR) and other angiogenic factors have also been examined. Tumor progression after antiangiogenic treatment is inevitable, and effective salvage therapy is yet to be identified. Mechanisms of resistance to antiangiogenic therapy include activation of alternative proangiogenic pathways and increased tumor invasion. Strategies targeting these escape mechanisms are currently being investigated. The use of antiangiogenic drugs is generally well tolerated, although rare and potentially life-threatening adverse effects have been identified. With the striking antipermeability effect of anti-VEGF inhibitors, assessment of true tumor response has become a challenge. The Response Assessment in Neuro-Oncology Working Group has developed new criteria for clinical trials in patients with high-grade glioma. Identification of neuroimaging advances and biologic markers will greatly enhance treatment strategies for these patients.

Angiogenic inhibition in high-grade gliomas: past, present and futureExpert Rev. Neurother. 12(6), 733–747 (2012)

Keywords: angiogenesis • bevacizumab • biomarkers • glioma stem cells • high-grade glioma • VEGF • VEGFR tyrosine kinase inhibitors

Expert Review of Neurotherapeutics

2012

12

6

733

747

© 2012 Expert Reviews Ltd

10.1586/ERN.12.53

1473-7175

1744-8360

Antiangiogenic therapies for high-grade glioma

Jo, Schiff & Purow

Expert Rev. Neurother.

Review

For reprint orders, please contact [email protected]

Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Mic

higa

n U

nive

rsity

on

11/0

6/14

For

pers

onal

use

onl

y.

Expert Rev. Neurother. 12(6), (2012)734

Review

present evidence and future challenges of antiangiogenic therapy in high-grade gliomas. This review will focus on therapies targeting VEGF and the VEGF receptor (VEGFR), which appear to be the major angiogenic factors in GBM and are the most studied.

Tumor angiogenesisAngiogenesis in brain tumorsThe formation of new blood vessels, which occurs both physi-ologically and pathologically, involves two processes [12]. During embryonic development, new blood vessels are formed from the mesoderm by differentiation of angioblasts into primitive vas-cular plexus, a process termed ‘vasculogenesis’ [13]. Subsequent sprouting and splitting of pre-existing vessels results in further growth and expansion of blood vessels, known as ‘angiogenesis’. In adults, physiologic angiogenesis occurs during reproductive cycles in females and in wound healing. Pathologically, the angio-genic process is stimulated in conditions that demand increased delivery of oxygen and nutrients such as in ischemic diseases, inflammatory conditions, diabetes and malignancy [14]. In 1966, Folkman et al. first showed that tumor growth and metastasis required the formation of new blood vessels [15]. Tumors are able to grow up to a size of approximately 2 mm3 before new vasculature is needed to support nutrient and oxygen supply [16]. On the basis of this concept, blocking angiogenesis as an anticancer strategy was first postulated in 1971 [17].

High-grade gliomas, especially GBM, are among the most highly vascularized tumors. Glioma angiogenesis ensues in a complex and coordinated manner. The initial development and late progression of brain tumors both involve co-option of nearby blood vessels. This allows tumor cells to migrate along existing blood vessels and to travel away from the solid tumor to infiltrate white matter tracts and cortical areas. Expression of angiopoietin (Ang)-2 causes destabilization of vessel walls and decreased pericyte coverage, which eventually causes vascular regression by apoptotic mechanisms due to disrupted interac-tions between endothelial cells (ECs), surrounding extracellular matrix and supporting cells [18,19]. Hypoxia and necrosis ensue, with prompt expression of hypoxia-inducible factor-1α (HIF-1α). This leads to upregulation of angiogenic factors such as VEGF by the glioma cells, which flips the ‘angiogenic switch’ and induces neovascularization (Figure 1) [20–24]. These newly formed tumor vessels are structurally and functionally abnormal, with disorgan-ized interconnections and a compromised blood–brain barrier (BBB). This causes unstable blood flow and efflux of proteins into the interstitial space, leading to further hypoxia, acidosis and increased intracranial pressure [25,26].

Mediators of angiogenesisVEGF plays a predominant role in high-grade glioma angiogen-esis. The VEGF gene family is composed of six glycoproteins: VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E and PlGF. VEGF-A (also known as VEGF) binds to two receptor tyrosine kinases, VEGFR-1 (Flt-1) and VEGFR-2 (KDR, Flk-1). VEGF-B and PlGF bind to VEGFR-1, VEGF-E binds to VEGFR-2, and

VEGF-C and -D bind to VEGFR-3. Proteolytically cleaved forms of VEGF-C and D may also bind to VEGFR-2 [27]. VEGFR-1 and VEGFR-2 are mainly expressed on vascular ECs and hemat-opoietic cells, and are involved in angiogenesis, whereas VEGFR-3 is mainly expressed in lymphatics and is involved in lymphangi-ogenesis (Table 1) [28]. VEGFR-2 activation plays a central role in angiogenesis by promoting EC proliferation. Conversely, VEGFR-1 expression and activation during angiogenesis regulate VEGFR-2-induced cell growth [29]. Neuropilins, which are non-tyros-ine kinase co-receptors, enhance the binding of VEGF to VEGFR-1 and VEGFR-2, thereby potentiating the angiogenic process [30]. The VEGFR-1 and -2 within the tumor vasculature activate the Ras/MAPK and PI3/Akt signaling pathways, which are impli-cated in GBM tumorigenesis. VEGF is the most studied and serves as perhaps the key regulator of angiogenesis. It is found to be elevated by tenfold in high-grade gliomas when compared with low-grade gliomas [31]. Both VEGF and its main receptor VEGFR-2 are expressed in high-grade glioma cells, resulting in a paracrine loop that promotes cell proliferation, survival, acti-vation, invasion, migration and permeability [32]. Production of these angiogenic factors is most concentrated adjacent to areas of pseudopalisading cells around the necrotic areas in GBM, as well as in the infiltrating cells surrounding the tumor [33]. Expression levels of VEGF are positively correlated with malignant pro-gression and vascular density [34]. VEGF signaling also stimu-lates recruitment of bone marrow progenitor cells that secrete proangiogenic factors to sites of ongoing tumor angiogenesis [35].

In addition to VEGF, an array of other proangiogenic factors are produced by GBM cells, contributing to angiogenesis. These include Ang-1 and Ang-2 [36,37], FGF [38,39], PDGF [40,41], EGF/TGF-α [42], TGF-β [43–45], SF/HGF, IL-6 and IL-8, and TNF-α [46–53]. Stromal cell-derived factor-1 (SDF-1/CXCL12) and its receptor, CXC chemokine receptor 4, regulates leukocyte and EC migration, bone marrow myelopoiesis and angiogenesis (Table 2) [21]. Factors that induce EC adhesion and invasion are also overex-pressed in high-grade glioma, including cysteine-rich angiogenic inducer 61, CTGF, IGF-1 [52], integrins [54,55] and matrix metal-loproteinases (MMPs) [56]. These angiogenic factors are potential targets for the treatment of GBM.

Recent research studies have identified the role of glioma stem-like cells (GSCs) in GBM progression and therapeutic resistance. GSCs are a subpopulation of GBM cells that share characteristics with normal neural stem cells, with the capacity for self-renewal, differentiation and proliferation [57–62]. These cells promote tumor angiogenesis via production of angiogenic factors, including VEGF [63]. They reside in a perivascular niche within the tumor, and thus antiangiogenic therapies that disrupt the tumor microenvironment, such as bevacizumab, may also function as anti-GSC strategies [64]. Mechanisms by which GSCs self-renew and divide in recurrent high-grade gliomas have been elucidated. GSCs are generated via symmetric and asymmetric cell division. Symmetric stem cell expansion occurs more frequently in the presence of growth factors and increases the GSC pool in the tumor. In the absence of growth factors, asymmetric cell division maintains the GSC pool by generating one CD133high daughter

Jo, Schiff & Purow

Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Mic

higa

n U

nive

rsity

on

11/0

6/14

For

pers

onal

use

onl

y.

735www.expert-reviews.com

Review

cell with stem cell capability and one non-GSC [65]. Prominin/ CD133+ brain cells can differentiate into neurons and glial cells in vitro [66].

Antiangiogenic therapies in high-grade gliomasMechanisms of VEGF inhibitionAntiangiogenic agents have several puta-tive antineoplastic mechanisms [67]. First, some antiangiogenic therapies block neoangiogenesis by inhibiting the VEGF pathway, depriving tumors of nutrients and oxygen needed for growth [68]. Second, inhibition of the VEGF pathway causes transient reversal of the vessel leakiness and sluggish blood flow caused by dysfunctional tumor vascula-ture, a phenomenon called ‘vessel nor-malization’ [69]. Third, these agents cause pruning of immature blood vessels, leav-ing behind the mature, functional ones. These latter two mechanisms transiently normalize perfusion, reduce hypoxia and thus induce tumor cell re-population. Administration of chemotherapy during this period results in improved drug deliv-ery of chemotherapy and increases killing of tumor cells in the proliferative phase [70]. Fourth, antiangiogenic therapy can counteract the surge of VEGF following radiation and chemotherapy [71,72]. Fifth, antiangiogenic drugs augment the anti-vascular effects of chemotherapy. These cytotoxic drugs affect tumor vascula-ture by destroying subsets of tumor ECs that proliferate dur-ing angiogenesis and also by myelosuppressive effects, thereby impairing the mobilization, function and viability of circulating bone marrow-derived endothelial progenitor cells [73,74]. Finally, antiangiogenic agents disrupt the vascular niches, which poten-tially compromises survival of GSCs [64]. In a high-grade glioma model, bevacizumab specifically abolished the proangiogenic effects of GSCs [75].

Anti-VEGF inhibition in high-grade gliomasVEGF inhibitorsBevacizumab is a recombinant humanized monoclonal antibody that binds all isoforms of VEGF [76]. Although a large molecule such as the antibody bevacizumab does not cross an intact BBB, this is not a concern because only intravascular delivery is required for binding to VEGF ligands, and the target ECs in the vascular niches are located on the vascular side of the BBB [68]. After the FDA approval of bevacizumab in combination with irinotecan (CPT-11) and 5-FU for metastatic colorectal cancer in 2004 [77], several studies have investigated its use in high-grade glioma. In

2005, a retrospective series using bevacizumab and irinotecan in 29 patients with recurrent high-grade glioma showed partial radiographic response in 16 out of 29 (55%) patients and complete response in three out of 29 (10%) patients. This regimen showed acceptable safety, with one patient developing bowel perforation and another patient developing intracranial hemorrhage [78]. A second series consisting of 14 patients with recurrent high-grade gliomas receiving bevacizumab with carboplatin, etoposide or irinotecan showed a favorable radiographic response in seven out of 14 (50%) individuals [79]. With the promising results of these

Glioma

Extracellular matrix VEGF and other

proangiogenic factors

Blood vesselEndothelial cells

PDGFPericytes

Ang-1/Tie-2 and TGF-β

MMP and Ang-1

Expert Rev. Neurother. © Future Science Group (2012)

Figure 1. With the ‘angiogenic switch’, tumor cells express vascular endothelial growth factor and other proangiogenic factors. Bone marrow-derived endothelial progenitor cells also secrete proangiogenic factors. Upon binding of these factors to their cognate receptors, pre-existing blood vessels dilate and become leaky. Endothelial cell (EC) proliferation, migration and assembly then follow. Local degradation of the vascular basement membrane and extracellular matrix ensues, mediated by the proteinases such as MMPs and Ang-2. This paves the way for migration of ECs into the extracellular matrix. Integrins αvβ3 and αvβ5 mediate EC adhesion, motility and invasion. ECs align in a bipolar mode, which then form a lumen. PDGF recruits new pericytes along the ECs outside the lumen. Ang-1/Tie-2 receptors and TGF-β regulate the interaction of EC and smooth muscle cells. Proteinase inhibitors, such as plasminogen activator inhibitor-1, prevent degradation of extracellular matrix around the newly formed vessels. Ang: Angiopoietin; MMP: Matrix metalloproteinase.

Table 1. Vascular endothelial growth factor and its ligands.

VEGF ligands VEGFRs Functions

VEGF-A, -B and PlGF VEGFR-1/(Flt-1)† Angiogenesis

VEGF-A, -B, -E VEGFR-2/(KDR, Flk-1) Angiogenesis

VEGF-C, -D VEGFR-3 Lymphangiogenesis†VEGFR-1 is a functional antagonist to VEGFR-2.VEGFR: VEGF receptor.


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Mic

higa

n U

nive

rsity

on

11/0

6/14

For

pers

onal

use

onl

y.


Review

retrospective reports, the first prospective Phase II trial using bevacizumab and irinotecan, in 23 patients with GBM and nine patients with AG patients, was reported in 2007 [80]. Radiographic responses based on modified Macdonald criteria [81] were noted in 20 out of 32 patients (63%), 14 out of 23 (61%) in those with GBM and six out of nine (67%) in patients with AGs. Six-month progression-free survival (PFS) was 38% and 6-month overall survival (OS) was 72%. One notable finding in this study was the acceptable safety profile. No patient developed intracranial hemorrhage, three patients developed thromboembolic events and only one suffered from ischemic stroke. A follow-up Phase II study of 35 patients with recurrent GBM showed that 20 out of 35 (57%) had at least partial radiographic response, with 6-month PFS of 46% and 6-month OS of 77% [82]. A recent report showed that the 4-year OS of this trial was 11%, with one out of four patients alive remaining progression-free and three others with tumor progression who responded to a bevacizumab-containing regimen [83].

In May 2009, the FDA granted accelerated approval to bevacizumab as a single agent in the treatment of recurrent GBM, based on two Phase II studies. The first study was an open label, multicenter, randomized, noncomparative study

involving 167 patients with first or second relapse of GBM. Patients were randomly assigned to receive bevacizumab 10 mg/kg or bevacizumab plus irinotecan [9]. Efficacy was assessed by determining the 6-month PFS and objective response (OR), defined as complete or partial response on two consecutive MRIs obtained 4 or more weeks apart. In the bevacizumab cohort, 6-month PFS was 43% and OR was 28%, whereas in the bevacizumab plus irinotecan cohort, it was 50 and 37%, respectively. Median OS was 9.2 months for bevacizumab alone and 8.7 months in the combination arm. A trend of stable or decreasing dose of corticosteroid was noted [84]. The safety profile was acceptable, and the incidence of adverse effects was similar to that in previous trials. The most common adverse events were hypertension, convulsion, neutropenia and fatigue. Five patients developed intracranial hemorrhage, two (2.4%) who received bevacizumab alone and three (3.8%) who received combination treatment. Arterial and venous thromboembolism was noted in seven (8.4%) patients in the bevacizumab group and 13 (16.4%) in the combination group. Two patients who received bevacizumab plus irinotecan suffered Grade 3 gastrointestinal (GI) perforation. Recent data have been reported on the neurocognitive function (NCF) across time in this population. All patients underwent baseline NCF testing. For patients with OR, PFS >6 months or disease progression, the memory, visuomotor, scanning speed and executive function were evaluated at the time of OR, at 24 weeks and at the time of progression, respectively. The majority of patients who had independent radiology facility (IRF)-determined OR or PFS >6 months demonstrated stable or improved performance on all tests relative to baseline at the time of OR (bevacizumab alone: 75%, combination arm: 61%) or at week 24 (bevacizumab alone: 70%, combination arm: 69%). Conversely, patients who had disease progression showed evidence of neurocognitive decline (bevacizumab alone: 69%, combination arm: 56%) [85]. The second study was a single arm, single-institution trial, involving 48 patients with recurrent GBM [11]. Patients were treated with bevacizumab 10 mg/kg every 2 weeks until tumor progression. After progression, patients were treated with bevacizumab plus irinotecan. The 6-month PFS was 29%, median PFS was 16 weeks, 6-month survival rate was 57% and median OS was 31 weeks. Response rate based on Macdonald criteria was 35%, with one complete response and 16 partial responses. Fifty eight percent of the patients were able to reduce intake of corticosteroids by an average of 59% from baseline dose. The most common adverse effects were thromboembolic events in six (12.5%) and hypertension in six (12.5%) patients. No patients developed intracranial hemorrhage. The accelerated FDA approval of bevacizumab monotherapy was based on the objective tumor response rate in the GBM cohort from these two studies [86]. Metronomic etoposide combined with bevacizumab was evaluated in a Phase II study for recurrent high-grade glioma patients [87]. Among 27 patients with recurrent GBM, 6-month PFS was 44%, median PFS was 18 weeks, radiographic response was 37% and median survival was 44 weeks – figures similar to the outcome in patients treated with bevacizumab plus irinotecan. This regimen is associated with increased toxicity compared with

Table 2. Other angiogenic ligands and receptors.

Angiogenic signaling factors

Receptors Effects on angiogenesis

Ang-1 Tie2 Stabilization, remodeling, maturation of blood vessels

Ang-2 Tie2 Destabilization of blood vessels

bFGF FGFR Induces VEGF expression

PDGF-β PDGFR-β Recruits pericytes; maturation of blood vessels

EGF and TGF-α EGFR Stimulates VEGF expression

SF/HGF c-MET EC migration and tube formation

IL-6 STAT3 Induces transcrip-tional activation of VEGF

IL-8 CXCR1, CXCR2, DARC

EC tubular formation

TNF-α TNFR Activates other angiogenic factors (VEGF, IL-8, bFGF)

SDF-1 CXCR4 EC survival and endothelial stem cell migration

Ang: Angiopoietin; EC: Endothelial cell; EGFR: EGF receptor; FGFR: FGF receptor; PDGFR: PDGF receptor; TNFR: TNF receptor.

Jo, Schiff & Purow

Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Mic

higa

n U

nive

rsity

on

11/0

6/14

For

pers

onal

use

onl

y.


Review

previously reported adverse effects from bevacizumab alone. Significant hematologic toxicities were Grade 3 or 4 anemia and thrombocytopenia in 24% of patients, but responded to dose modification. The most common serious nonhematologic events were thrombosis (12%), infection (8%) and hypertension (3%).

With the encouraging response rates associated with beva-cizumab treatment in recurrent GBM, two large randomized double-blind, placebo-controlled Phase III trials (RTOG 0825 and AVAGLIO) are presently being conducted to evaluate the efficacy and safety of adding bevacizumab to the current stand-ard of treatment (concurrent chemoradiation and adjuvant temo-zolomide) for newly diagnosed GBM [88]. The co-primary end points of these studies are to demonstrate improvements in the PFS and OS.

Bevacizumab has also undergone evaluation for the treat-ment of recurrent AGs. A Phase II trial using bevacizumab with irinotecan in 33 patients with recurrent Grade 3 high-grade glioma reported a 6-month PFS of 55%, 6-month OS of 79%, median OS of 31 weeks and that 61% had partial radiographic response. One patient developed intracranial hemorrhage and another patient had thrombotic thrombocytopenic purpura [89]. The same regimen was retrospectively evaluated in 25 patients with recurrent oligodendroglial tumors, yielding a response rate of 72% [86]. However, the PFS was less striking, with a median PFS of 4.6 months and 6-month PFS of 42%. After a median follow-up of approximately 7 months, OS was not reached. No relationship was found between response rate and the tumor’s genetic phenotype, including 1p/19q co-deletion. Six patients (24%) developed intratumoral hemorrhages, which is considered a high rate compared with previous reports of GBM patients [9,11,83]. The addition of metronomic etoposide to bevacizumab was evaluated in 32 patients with AG [87]. The 6-month PFS (41%) and response rate (22%) were comparable with combina-torial bevacizumab plus irinotecan given in the same population [89]. The use of single-agent bevacizumab was recently evaluated in 30 patients with recurrent AG, and demonstrated 13 (43%) partial responses, median OS of 12 months and 6-month PFS of 21%. This study showed a significant benefit in terms of radio-graphic response, as seen in GBM patients, but the 6-month PFS end point was not achieved [90]. Clinical experience with the use of bevacizumab in AGs has not shown impressive PFS and OS when compared with the corresponding outcomes in GBM patients.

Several Phase II trials and retrospective series evaluated the activity of bevacizumab plus chemotherapy in recurrent high-grade gliomas. For patients with recurrent GBM, the 6-month PFS, median PFS, median OS and radiographic response were 22–64%, 16–30 weeks, 27–46 weeks and 23–83%, respectively; whereas for patients with AG, the corresponding values were 32–79%, 30–54 weeks, 31–63 weeks and 24–71%, and for both MG the values were 25–46%, 19–20 weeks, 28–50 weeks and 44–47%, respectively [87,89,91–98]. A Phase II study evaluated treat-ment with bevacizumab and the EGF receptor tyrosine kinase inhibitor erlotinib in patients with recurrent high-grade glioma [99]. This study showed similar 6-month PFS (28%), median PFS

(18 weeks), median OS (45 weeks) and radiographic response (50%) to other bevacizumab-containing regimens in patients with recurrent GBM. In patients with AG, the 6-month PFS (44%) and response rate (31%) were comparable to patients given bevazicumab plus cytotoxic chemotherapy. Improved 6-month PFS, median PFS (23 weeks) and median OS (71 weeks) were observed when compared with patients with recurrent AG who were receiving bevacizumab alone [90]. The safety and activity of bevacizumab in combination with hypofractionated stereotactic radiotherapy was also investigated. The outcome was comparable to that achieved with single-agent bevacizumab, with a 6-month PFS of 65%, median PFS of 29 weeks, median OS of 50 weeks and radiographic response of 50% for patients with recurrent GBM. Corresponding values for recurrent AG were 60%, 30 weeks, 66 weeks and 60%, respectively. The overall toxicity was in line with other reports of bevacizumab use [100]. No trials to date have shown benefit from adding a second agent to bevacizumab in patients with recurrent GBM. However, in Hs683 human GBM orthotopic xenograft-bearing immunodeficient mice, the addi-tion of bevacizumab to temozolomide significantly improved the therapeutic benefits of temozolomide compared with when each drug was administered alone [101]. For patients with recurrent AG, the combination of bevacizumab with cytotoxic agents such as irinotecan or etoposide, or a tyrosine kinase inhibitor such as erlotinib may be more beneficial compared with bevacizumab monotherapy [87,89,90,99]. Tables 3 & 4 show the summary of out-comes from bevacizumab trials in patients with recurrent GBM and AG.

A novel approach to targeting VEGF activity involves the scav-enging of VEGF ligand with a decoy receptor. Aflibercept, also known as VEGF trap, is a recombinant fusion protein, composed of the extracellular domains of VEGFR-1 and VEGFR-2 fused to the Fc portion of human immunoglobulin, which binds with high affinity to VEGF-A. It also binds to VEGF-B and PlGF, which are also implicated in tumor angiogenesis [102]. A preclini-cal study in an orthotopic GBM model found that VEGF trap significantly prolonged the survival of glioma xenograft-bearing mice [103]. A single-arm Phase II trial evaluated aflibercept at 4 mg/kg given every 2 weeks in 42 patients with recurrent GBM and 16 patients with recurrent AG. The recently published results indicated that aflibercept has minimal activity in recurrent high-grade glioma, with a 6-month PFS of 7.7% for GBM and 25% for AG [104]. These numbers were lower than correspond-ing reported rates in single-agent bevacizumab trials [9,11]. The radiographic response rate was 18% for GBM and 44% for AG. Dynamic contrast-enhanced MRI showed a rapid decrease in permeability, but was not predictive of durable response or time to progression (TTP). The most common adverse effects were Grade 3 hypertension, lymphopenia and fatigue. Two patients experienced Grade 4 CNS ischemias and one developed Grade 4 GI bleeding [104].

A preclinical study of VEGF trap in combination with radiotherapy in U87 GBM xenografts in nude mice showed a significant reduction in tumor growth over radiotherapy alone [105]. On the basis of this observation, a Phase I trial of


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Mic

higa

n U

nive

rsity

on

11/0

6/14

For

pers

onal

use

onl

y.


Review

aflibercept with radiation therapy plus concomitant and adjuvant temozolomide in patients with high-grade glioma is currently ongoing [201].

VEGFR inhibitorsInhibitors of VEGF tyrosine kinase receptors are small molecules that competitively block tyrosine or serine/threonine kinase domains [106]. Cediranib (AZD2171) is an oral pan-VEGFR, PDGF receptor (PDGFR) and c-Kit inhibitor [107]. A Phase II trial of 16 patients with recurrent GBM treated with cediranib 45 mg daily demonstrated rapid normalization of tumor vasculature and alleviation of vasogenic edema. The effect lasted for 28 days, which suggests concurrent chemotherapy and radiotherapy may be beneficial within this window of opportunity [108]. Another Phase II trial evaluated cediranib in 31 patients with recurrent GBM and reported 6-month PFS of 25.8% and radiographic partial response of 56.7%. Grade 3–4 adverse effects included hypertension, diarrhea and fatigue. Intracranial hemorrhage was not observed. Fifteen patients were on corticosteroids at baseline

and ten of these patients were able to reduce the dose and five discontinued its use [109]. Recently, a large Phase III multicenter study randomized 325 patients with recurrent GBM to either cediranib monotherapy 30 mg/d (n = 120), the combination of cediranib 20 mg/d with lomustine 110 mg/m2 every 6 weeks (n = 120) or lomustine alone (n = 60). The primary end point was PFS, and the study found no statistically significant difference in the median PFS of 92 days in cediranib arm or 125 days in combination arm compared with median PFS of 82 days in the control arm. The 6-month PFS in the cediranib cohort was 16%, lower than in the previous Phase II study. The hypothesized rea-son was the lower dose used in the randomized trial. The overall study results were assessed as negative [110].

Sunitinib is a tyrosine kinase inhibitor targeting VEGFR2, KIT and PDGFR-α. Results of a Phase II study of sunitinib in patients with recurrent high-grade glioma were recently reported. Twenty-one patients received sunitinib 37.5 mg daily until tumor progression or unacceptable toxicity. The median TTP and OS were only 1.6 and 3.8 months, respectively. Decreased cerebral

Table 4. Outcomes from bevacizumab treatment trials in recurrent anaplastic glioma.

Therapeutic agents/population

Complete radiographic response (%)

Partial radiographic response (%)

PFS at 6 months (%)

Median PFS (weeks)

Median OS (weeks)

Ref.

BEV + irinotecan (n = 33)

61 55 30 65 [89]

BEV + irinotecan or carboplatin or carmustine or temozolomide (n = 21)

NR NR 32 NR NR [98]

BEV + etoposide (n = 32)

7 17 41 24 63.1 [87]


14 64 79 54 Not reached [93]

BEV (n = 31) 0 43 21 12 48 [90]

BEV: Bevacizumab; NR: Not reported; OS: Overall survival; PFS: Progression-free survival.

Table 3. Outcomes from bevacizumab treatment trials in recurrent glioblastoma.

Therapeutic agents/population

Complete radiographic response (%)

Partial radiographic response (%)

PFS at 6 months (%)

Median PFS (weeks)

Median OS (weeks)

Ref.


4 57 30 20 40 [80]


57 46 24 42 [82]


2 35 15 9 25 [9]

BEV alone (n = 85) 1 27 43 17 37 [9]

BEV alone (n = 48) 1 33 29 16 31 [11]

BEV + etoposide (n = 27) 4 19 44 18 46 [87]

BEV + erlotinib (n = 25) 4 46 29 18 44.6 [99]

BEV + HFSRT (n = 20) 50 65 29 50 [100]

BEV: Bevacizumab; HFSRT: Hypofractionated stereotactic radiotherapy; OS: Overall survival; PFS: Progression-free survival.

Jo, Schiff & Purow

Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Mic

higa

n U

nive

rsity

on

11/0

6/14

For

pers

onal

use

onl

y.


Review

blood volume and cerebral blood flow were noted in 29% of patients, but none of the patients showed an objective response. Common adverse effects encountered were Grade ≥3 skin toxic-ity, neutropenia, thrombocytopenia and lymphopenia [111].

Pazopanib, a multitargeted tyrosine kinase inhibitor against VEGFR-1, -2 and -3, PDGFR-α and -β and c-Kit, was investigated in a Phase II trial as monotherapy for 35 patients with recurrent GBM. The median PFS was 3 months. Only one patient (3%) had PFS beyond 6 months and only two (6%) achieved partial radio-graphic responses. Grade 3–4 toxicities resembled those seen with other antiangiogenic agents. One patient developed intracranial hemorrhage and three experienced thromboembolic events [112].

Encouraging results were reported from a Phase II trial using XL-184 (Cabozantinib) in patients with recurrent GBM. This oral agent produced by Exelixis (CA, USA) inhibits HGF receptor (MET), VEGFR2 and c-kit. HGF/SF and its receptor MET are expressed in glioma cells and are associated with malignant pro-gression and angiogenesis [46]. Forty-six patients received 175 mg orally po daily, 26 of whom were available for response assessment. A total of 38% demonstrated a ≥50% radiographic reduction, with one patient achieving 100% reduction. Updated safety and efficacy results will soon be reported [113]. Frequent dose interruptions and reductions were made in this study due to adverse effects, which included fatigue, elevated ALT, anorexia and hand–foot syndrome.

Several other clinical trials involving multikinase VEGFR inhibitor agents for high-grade gliomas are being investigated and awaiting final reports. Table 5 shows the summary of clinical trials involving antiangiogenic agents for high-grade gliomas [202].

Toxicities of antiangiogenic therapyClinical trials of antiangiogenic therapies have demonstrated a generally acceptable safety profile, primarily because they act

more selectively than cytotoxic agents [114]. However, there are distinct toxicities that complicate care. Common adverse effects include hypertension and proteinuria, poor wound healing, and venous and arterial thromboembolic events [115]. Hypertension is a commonly encountered adverse effect seen with the use of anti-VEGF agents. Inhibition of the VEGF pathway decreases production of nitric oxide, a potent vasodilator, and thus promotes vasoconstriction. In addition, these agents induce a functional decrease in the number of arterioles and capillaries. In concert, these effects cause an increase in peripheral vascular resistance, resulting in hypertension [116]. Hypertension can induce proteinuria by increasing intraglomerular pressure [117]. There is also evidence that VEGF inhibition has a direct toxic effect on glomerular podocytes, producing thrombotic microangiopathy [118]. Hypertension and proteinuria are usually reversible upon discontinuation of antiangiogenic treatment. On rare occasions, acute hypertension may cause posterior reversible encephalopathy syndrome due to the disturbance of the regulation of cerebral blood flow and dysfunction of the BBB causing cerebral edema [119]. Anti-VEGF therapy also seems to increase the incidence of thrombosis by increasing EC apoptosis, which disturbs the endothelial lining and exposes underlying pro-coagulant factors [116]. In the study by Friedman et al. of 167 patients with recurrent GBM, 8% of patients who received bevacizumab alone and 16% of patients who received bevacizumab and irinotecan developed arterial and venous thromboembolisms [9]. Rare but potentially life-threatening adverse effects with the use of antiangiogenic agents include intracranial hemorrhage and GI perforation. In the same study, two (2.4%) patients who received single-agent bevacizumab experienced Grade 1 intracranial hemorrhage, and three (3.8%) who received bevacizumab plus irinotecan experienced Grades 1, 2 and 4 intracranial hemorrhage, respectively. Two (2.5%) patients

Table 5. Antiangiogenic agents under study in high-grade glioma.

Agents Targets Trials

CT-322 (Angiocept) VEGFR-2 Phase I; NDGBM

ABT510 Thrombospondin-1 Phase I; NDGBM

Sunitinib (SU011248) VEGFR-2, KIT and PDGFR-α Phase I; recurrent high-grade glioma

RO5323441 PlGF-1 and -2 Phase I/II; recurrent GBM

Sorafenib VEGFR and RAF kinase Phase II; NDGBM

Sunitinib VEGFR-2 and PDGFR-β Phase II; NDGBM

Amgen 386 Ang-1 and -2 Phase II; recurrent GBM

Intedanib (BIBF 1120) VEGFR 1–3, PDGFR-α and -β, FGF 1–3, FLT3, and Src Phase II; recurrent high-grade glioma

Cilengitide (EMD121974) αvβ3 and αvβ5 Phase II; recurrent GBM

Enzastaurin PKC-β Phase II; recurrent high-grade glioma

Vandetanib (ZD6474) VEGFR, RET and EGFR Phase II; recurrent high-grade glioma

BKM 120 PI3K Phase II; recurrent GBM

Rilotumumab (AMG 102) HGF inhibitor Phase II; recurrent high-grade glioma

Tandutinib (MLN 518) PDGFR-A Phase II; recurrent high-grade glioma

Ang: Angiopoietin; EGFR: EGF receptor; GBM: glioblastoma; NDGBM: Newly diagnosed GBM; PDGFR: PDGF receptor; VEGFR: VEGF receptor.


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Mic

higa

n U

nive

rsity

on

11/0

6/14

For

pers

onal

use

onl

y.


Review

in the combination group had Grade 3 GI perforation [9]. Another adverse effect that could potentially complicate neurosurgical care is its effect on wound healing. Inhibition of the VEGF pathway impairs neovascularization, disturbs platelet–EC interaction and reduces VEGF-induced tissue factor on ECs [120]. Grade ≥3 wound healing complications occurred in 2.4% of patients who received bevacizumab monotherapy, and in 1.3% of patients who received combination therapy [9].

Anti-VEGF agents target ECs in the vascular niches. These ECs are critical components of the neural stem cell niche that maintain CNS stem cell self-renewal, and thus generation of new neurons, astrocytes and oligodendrocytes [121]. Compromising survival of these progenitor cells theoretically could cause neurotoxicity, producing leukoencephalopathy and cognitive impairment [122]. In a recent report, the majority of patients who participated in the BRAIN study with IRF-determined OR and PFS >6 months showed improved or stable NCF at the time of response or at 24-week assessment, respectively [85].

Escape mechanismsPatients who initially respond to antiangiogenic treatments almost inevitably develop tumor progression. This suggests that tumor cells are able to escape inhibition of the VEGF pathway. Two general mechanisms of resistance to angiogenic inhibition are hypothesized. First is the adaptive or evasive mode of resistance and second is the presence of an intrinsic or pre-existing resist-ance of tumor cells, owing to their stage of progression, treatment history, genomic constitution and/or host genotype [123].

In order for tumors to evade or adapt to blockage of angiogenesis, they acquire several alternative means to sustain tumor survival and growth. One mechanism is the ability of tumor cells to adapt to the hypoxia induced by blocking of the VEGF pathway [203]. Hypoxia causes upregulation of HIF-1α, which promotes mobilization of bone marrow-derived endothelial precursor cells and production of alternative proangiogenic factors [124,125]. Elevations in VEGF, as well as a dose-dependent increase in proangiogenic factors including PlGF, SDF1α (or CXCL12), granulocyte-colony stimulating factor (or CSF3), TGF-α, stem cell factors (or KIT ligand) and osteopontin were observed in a preclinical orthotopic GBM model treated with sunitinib [126]. In patients with recurrent GBM who received cediranib, a similar elevation of angiogenic factors was also seen at the time of progression [108]. Recruitment of bone marrow-derived CD45+ myeloid cells including TIE2+, VEGFR-1+, CD11b+ and F4/80+ subpopulations, as well as endothelial and pericyte progenitor cells promote neovascularization in orthotopic mouse model of GBM. CD45+ myeloid cells carry and secrete MMP-9 to the tumor site, which makes sequestered VEGF bioavailable for binding to its receptor, VEGFR2, for neovascularization [124]. Another adaptive mechanism is increasing pericyte coverage to protect tumor blood vessels [123]. Increased PDGF signaling induces a recruitment of pericytes, resulting in stabilization of new tumor vessels via the Ang-1/Tie2 pathway. Inhibition of both VEGFR-2 and PDGFR-β produces rapid tumor vessel

regression by the additional inhibition of the pericyte-associated survival mechanism [127]. Targeting these alternative pathways represents one potential approach to overcome the resistance to anti-VEGF/VEGFR. Agents that address these concerns are being investigated, such as indetanib (VEGFR, PDGFR and FGF inhibitor), brivanib (VEGFR and FGFR inhibitor), XL-184 (VEGFR and c-MET inhibitor), plerixafor (CXCR4 inhibitor) and Amgen 386 (Ang-1 and -2 inhibitor) [125]. In addition, mammalian target of rapamycin (mTOR) inhibitors have been shown to block HIF-1α production. Some patients with renal cell carcinoma resistant to targeted antiangiogenic agents have shown significant benefit from administration of the mTOR inhibitor everolimus [128]. However, both single-agent studies of temsirolimus and the combination of sorafenib with temsirolimus showed limited activity in recurrent GBM [129]. Growing evidence suggests that inhibition of the VEGF-dependent neovascularization in GBM results in a more invasive tumor phenotype. In an orthotopic GBM model, genetically deleting the angiogenic regulators VEGF, HIF-1α or MMP-9 caused tumor cells to become more motile and to disperse deep into the brain parenchyma by moving along the perivascular spaces of normal blood vessels, referred to as perivascular tumor invasion [130]. This signified an aggressive infiltrative pattern without signs of angiogenesis [131]. In another GBM xenograft model, antiangiogenic therapy caused a metabolic shift in the tumor towards the glycolytic pathway, together with induction of HIF-1α, leading to enhanced cell invasion into the normal brain [132]. Some clinical reports suggest a nonenhancing and multifocal pattern of tumor progression after treatment with bevacizumab for patients with GBM, and this pattern correlates with worse survival [93,131,133]. These imaging findings are in contradistinction to the typical enhancing pattern with vasogenic edema seen in aggressive gliomas. In a series of five patients, upregulation of invasive markers, as well as mesenchymal and hematopoietic stem cell markers were associated with antiangiogenic treatment [134]. A recent report argues against this specific property of bevacizumab. This study demonstrated that the risk of distant or diffuse tumor spread at the time of failure of bevacizumab-containing regimens was not higher than with anti-VEGF free regimens [135]. The same observation was reported from an evaluation of the patterns of tumor recurrence in patients with recurrent GBM who participated in the BRAIN study. A greater proportion of patients who received bevacizumab alone (82%) demonstrated no change in the radiographic pattern of their tumor at the time of progression than those who received bevacizumab plus irinotecan (39%). Furthermore, patients in either treatment group who had local-to-local or local-to-diffuse progression patterns had similar outcomes, including OR, PFS and OS. This study, however, did not have a cohort for irinotecan alone, preventing definite evaluation of whether the diffuse and distant pattern of GBM progression is attributable to bevacizumab [136].

In patients who did not show a discernable, even transitory, ben-eficial response to angiogenic inhibition, an intrinsic pre-existing nonresponsiveness of tumor cells is hypothesized. Speculative

Jo, Schiff & Purow

Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Mic

higa

n U

nive

rsity

on

11/0

6/14

For

pers

onal

use

onl

y.


Review

mechanisms of this type of resistance include: pre-existing multi-plicity of redundant proangiogenic signals; pre-existing infiltration of inflammatory cells, principally CD11b+Gr1+ myeloid cells; char-acteristic hypovascularity and indifference toward angiogenesis inhibitors; and when tumor cells have already switched on highly invasive capabilities early in their ontogeny without requisite of angiogenesis [123].

Assessment of tumor responseThe era of antiangiogenic therapy has created new challenges in the evaluation of tumor response. Most high-grade glioma trials utilize radiographic response, together with PFS, as end points. Assessment based on symptomatic response may not be reliable, as it is subjective and may not be directly related to the tumor itself [125]. The Macdonald criteria have long been used for the assessment of tumor response in these trials [81]. These rely upon measurement of the extent of contrast enhancement of the lesions, as well as corticosteroid use and clinical function. In most studies, significant improvement in the enhancement of these tumors has been observed after antiangiogenic therapy. However, the striking radiographic response may not correlate with improvement in PFS and OS [82]. In some patients, progressive nonenhancing tumor infiltration was seen in the T2/FLAIR sequences despite improvement in enhancement [98]. These findings raise questions over whether the improved enhancement reflects true tumor response or a ‘pseudo-response’ due to decreased permeability of tumor vasculatures. For these reasons, the Response Assessment in Neuro-Oncology (RANO) Working Group developed new standardized criteria for clinical trials in patients with high-grade glioma [137]. These criteria included measurement of T2/FLAIR nonenhancing lesions. However, the RANO group cautioned that changes in T2/FLAIR signal may also be seen with radiation effects, decreased corticosteroid intake, demyelination, ischemic injury, infection, seizures and postoperative changes. These T2/FLAIR changes most likely reflect infiltrating tumor if they cause mass effect, involve the cortical ribbon and appear outside the radiation field, or in the absence of other potential explanations.

BiomarkersAs shown by the numerous trials that evaluated antiangiogenic treatment for high-grade gliomas, only a subset of patients showed radiographic response and prolonged survival. Imaging parameters and biologic markers that could identify patients with tumors likely to respond or resist antiangiogenic therapy would greatly improve the treatment strategies for patients with high-grade gliomas.

Imaging parametersSeveral imaging techniques have been investigated to deter-mine the hemodynamic changes associated with antiangiogenic treatments. Dynamic contrast-enhanced-MRI is a noninvasive method for measuring properties of the tumor microvasculature. Dynamic contrast-enhanced-MRI utilizes a low molecular-weight paramagnetic contrast agent that readily diffuses from the blood to the extravascular extracellular space, providing information about blood volume, microvascular surface area and permeability

(Ktrans) [138]. A Phase II trial investigated the correlation among the vascular permeability (Ktrans), microvessel volume and clinical outcome in 31 recurrent GBM patients treated with cediranib. After a single dose of cediranib, a greater reduction in Ktrans was seen in patients with increased PFS and OS, and a greater increase in cerebral blood volume of tumor microvessels was seen in patients with extended OS. Combination of these two neu-roimaging biomarkers with the level of circulating collagen IV into a ‘vascular normalization index’ (VNI) demonstrated close association of this index with OS and PFS [139]. Thus, VNI can potentially be used to predict better outcome after anti-VEGF treatment. Diffusion-weighted imaging (DWI) and the related apparent diffusion coefficient (ADC) measure the mobility of water. Restricted diffusion is seen in highly cellular tumors. Contrast-enhancing and noncontrast-enhancing lesion ADC were evaluated in 20 patients with recurrent high-grade glioma treated with bevacizumab, and demonstrated different trends over time for nonprogressors and progressors. These findings sug-gest that DWI may be used as an additional imaging biomarker for early treatment response [140]. In a prospective evaluation involving 30 patients treated with cediranib, areas with low ADC were significantly suggestive of regions of infiltrative tumor cells. Thus, monitoring changes in ADC might be potentially useful in the assessment of recurrent GBM [141]. A study of 35 patients with newly diagnosed GBM who were given enzastaurin utilized dynamic susceptibility contrast MRI to assess vascular density and leakage, by measuring the percentage recovery and peak height. Six-month radiographic responders showed improvement in percent recovery at 2 months, and the nonresponders showed increased peak height at 1 month. These parameters may be used as an early predictor of radiographic response and may be predictive of progression [142]. Nucleic acid analogue radiotracer 18F-fluorothymidine (18F-FLT) is used as an indicator of cellular proliferation. A prospective study performed 18F-FLT positron emission tomography scans in 19 patients with recurrent high-grade gliomas treated with bevacizumab and irinotecan. This study showed both early and late 18F-FLT responses were signifi-cant predictors of OS, and can be used as biomarkers of outcome as early as 6 weeks [143]. Evaluation of OR, as a predictor of survival in patients with recurrent GBM, was recently reported. Fifty five of 167 patients who participated in the BRAIN study showed IRF-determined OR (bevacizumab alone: 24; bevaci-zumab plus irinotecan: 31). The OR at 9, 18 and 26 weeks was found to be a statistically significant predictor of survival. Thus, OR can be used as a reliable predictor of therapeutic benefit in these patients [144].

Circulating & tissue biomarkersAnti-VEGF inhibition with cediranib is associated with significant increases in plasma VEGF and PlGF and a decrease in soluble VEGFR-2 during treatment. At tumor progression, PlGF level decreases whereas soluble VEGFR-2, bFGF and SDF-1α increases. During drug holidays, elevated bone marrow-derived endothelial precursor cells have been associated with radiographic progression [65]. A greater increase in circulating collagen IV levels, a parameter


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Mic

higa

n U

nive

rsity

on

11/0

6/14

For

pers

onal

use

onl

y.


Review

included in VNI, was associated with extended PFS in GBM patients treated with cediranib [139]. An increase in markers of hypoxia including the HIF-2α and the hypoxia-inducible transmembrane enzyme carbonic anhydrase 9 (CA9) were associated with decreased OS [145]. However, in another study involving 21 patients treated with bevacizumab, molecular markers involved in angiogenesis, hypoxia and downstream signaling such as VEGF, EGFR, HIF-1α, CD34, CA9, GLUT-1, pAKT and PTEN were not predictive of response to anti-VEGF treatment [146]. The hypoxia markers CA9, HIF-1α and SMAD2 were found to be significantly associated with longer TTP in patients with recurrent GBM and AG treated with aflibercept [104]. A recent study also identified potential circulating markers in patients with recurrent GBM treated with aflibercept. Improved response was associated with lower baseline level of PlGF, elevated baseline levels of chemokines such as cutaneous T-cell attracting chemokine (CTACK/CCL27), macrophage chemotactic protein-3 (MCP-3/CCL7), macrophage migratory inhibitory factor and IFN-γ-inducible protein 10 (IP-10/CXCL10) and a decrease in VEGFR-1+ monocytes from baseline to 24 h. Increase in circulating MMP-9 was associated with tumor progression [147].

Silencing of the O6-methylguanine-DNA methyltransferase (MGMT ) gene has been associated with longer OS in patients who received adjuvant treatment for high-grade glioma. This benefit is seen across all subgroups of patients based on the type of chemo-therapy (temozolomide or nitrosurea containing), primary versus salvage treatment or tumor grade (Grade III or IV) [148]. Tumor angiogenic profile has been investigated in predicting radiographic response and/or survival in 45 high-grade glioma patients treated with bevacizumab and irinotecan. High tumor expression levels of VEGF was associated with increased likelihood of radiographic response but not survival benefit, while elevated CA9 was associ-ated with poor survival outcome [145]. CD133 expression in 37 recurrent GBM samples were increased by up to 20-fold com-pared with primary GBM and was surprisingly associated with longer survival. In this CD133+ high cell population, 20–60% was represented by the non-GSC. The heterogenous composi-tion of CD133+ high cells may help explain better survival than CD133+ low cells [149]. This is in contrast to the findings in ex vivo analysis of CD133+ primary GBM cells that presented with aggres-sive tumor behavior (promotion of angiogenesis and invasiveness) contributing to adverse prognosis [66].

Alternative dosingHigh doses of antiangiogenic agent reduce vascular permeability, which causes increased tumor hypoxia and necrosis. This produces a rapid initial tumor response due to vascular normalization and reduction of cerebral edema. However, over time, hypoxia may result in the development of a more invasive tumor phenotype.

A paradoxical relationship between the dose of antiangio-genic agents and overall benefit was recently demonstrated. In an orthotopic glioma model, the effects of antiangiogenic agent were dose dependent, but showed improved delivery of concomi-tant chemotherapy when given at lower doses [150]. Using lower doses or intermittent dosing schedules may delay onset of hypoxia,

improve delivery of coadministered drugs and ultimately improve patient survival [151].

Expert commentaryUnderstanding the biology of high-grade gliomas at the molecular level has identified the critical role of angiogenesis in the survival of these tumor cells. This knowledge led to the development of therapeutic agents that inhibit angiogenic pathways. Current evi-dence has shown promising radiographic responses and PFS with the use of anti-VEGF agents. Unfortunately, all patients eventually progressed, suggesting that GBM cells are able to escape VEGF inhibition. Potential mechanisms of resistance have been identi-fied, including activation of alternative proangiogenic pathways and increased tumor invasion. Inhibition of alternative angiogenic pathways has been investigated, but has not shown encouraging results to date. Several preclinical and clinical trials are currently being conducted to address these issues. Moreover, strategies to block tumor invasiveness need to be developed. Another challenge encountered with the use of antiangiogenic agents is the assessment of true tumor response. Apart from the RANO criteria, incorpo-ration of novel imaging hemodynamic parameters may improve assessment of biologic response of these tumors. In addition to imaging parameters, integration of neurocognitive function as an end point in future clinical trials might be useful in assessing clini-cal benefit from treatment. Validation of predictive biomarkers is needed to help identify patients who are likely to respond to or resist antiangiogenic treatment, leading to a ‘personalized’ treat-ment strategy. Determination of optimal dose, schedule and timing of antiangiogenic agents should also be investigated.

Five-year viewAngiogenic inhibition is expected to play a major role in future therapeutic approaches for high-grade gliomas. In 5 years, the challenges encountered with the use of anti-VEGF and VEGFR in high-grade gliomas will be addressed, which include: further understanding and identification of new strategies to circumvent escape mechanisms of GBM cells; incorporation of novel hemo-dynamic radiographic parameters in the assessment of tumor response; identification of biologic markers that can be used to select patients who will likely benefit from antiangiogenic treat-ment and to monitor treatment effects; determination of optimal biologic dose, schedule and timing of antiangiogenic medications; development of strategies to target tumor invasiveness after VEGF and VEGFR inhibition; utilization of antiangiogenic treatment in optimized combinations with chemotherapy, radiotherapy and/or other targeted molecular agents for high-grade gliomas.

Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or mater ials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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

Jo, Schiff & Purow

Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Mic

higa

n U

nive

rsity

on

11/0

6/14

For

pers

onal

use

onl

y.


Review

Key issues

• VEGF-A (also known as VEGF) and its cognate receptor VEGF receptor-2 are expressed in high-grade glioma cells and play a predominant role in glioma angiogenesis.

• Bevacizumab, a recombinant humanized monoclonal antibody, was approved by the US FDA as a single agent in the treatment of recurrent glioblastoma.

• An array of clinical studies investigating inhibition of VEGF, VEGF receptor and other proangiogenic factors in the treatment of high-grade glioma, both as upfront and as salvage therapy, are being conducted.

• Antiangiogenic therapy may also target glioma stem cells, which are self-renewing tumor cells that reside in perivascular niche and are an important source of proangiogenic factors.

• Antiangiogenic drugs have an acceptable safety profile, although potentially serious and life-threatening adverse effects including intracranial hemorrhage and thromboembolism have been reported.

• Tumor progression after antiangiogenic treatment is inevitable, and escape mechanisms with VEGF inhibition have been identified, including activation of alternative proangiogenic factors and increased tumor invasion.

• In addition to the Response Assessment in Neuro-Oncology criteria, parameters to assess true tumor response need to be developed.

• Identification and validation of neuroimaging and biologic markers will help identify patients who are likely to respond or resist antiangiogenic therapy.

ReferencesPapers of special note have been highlighted as:• of interest•• of considerable interest

1 CBRTUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2004–2007. Central Brain Tumor Registry of the United States (CBRTUS), Hinsdale, IL, USA (2011).

2 Stupp R, Mason WP, van den Bent MJ et al.; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups. National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med. 352(10), 987–996 (2005).

3 Stupp R, Hegi ME, Mason WP et al.; European Organisation for Research and Treatment of Cancer Brain Tumour and Radiation Oncology Groups. National Cancer Institute of Canada Clinical Trials Group. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised Phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 10(5), 459–466 (2009).

4 Prados MD, Gutin PH, Phillips TL et al. Highly anaplastic astrocytoma: a review of 357 patients treated between 1977 and 1989. Int. J. Radiat. Oncol. Biol. Phys. 23(1), 3–8 (1992).

5 Prados MD, Seiferheld W, Sandler HM et al. Phase III randomized study of radiotherapy plus procarbazine, lomustine, and vincristine with or without BUdR for treatment of anaplastic astrocytoma: final report of RTOG 9404. Int. J. Radiat. Oncol. Biol. Phys. 58(4), 1147–1152 (2004).

6 van de Bent MJ, Carpentier AF, Brandes AA et al. Adjuvant procarbazine, lomustine, and vincristine improves progression-free survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized European Organisation for Research and Treatment of Cancer Phase III trial. J. Clin. Oncol. 24, 2715–2722 (2006).

7 Yung WK, Albright RE, Olson J et al. A Phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse. Br. J. Cancer 83(5), 588–593 (2000).

8 Yung WK, Prados MD, Yaya-Tur R et al. Multicenter Phase II trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse. Temodal Brain Tumor Group. J. Clin. Oncol. 17(9), 2762–2771 (1999).

9 Friedman HS, Prados MD, Wen PY et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J. Clin. Oncol. 27(28), 4733–4740 (2009).

•• StudythatledtoacceleratedUSFDAapprovalofbevacizumabmonotherapyforrecurrentglioblastoma.

10 Avastin®, package insert. Genentech USA, Inc, CA, USA (2011).

11 Kreisl TN, Kim L, Moore K et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J. Clin. Oncol. 27(5), 740–745 (2009).

•• StudythatledtoacceleratedFDAapprovalofbevacizumabmonotherapyforrecurrentglioblastoma.

12 Carmeliet P. Angiogenesis in life, disease and medicine. Nature 438(7070), 932–936 (2005).

13 Risau W, Flamme I. Vasculogenesis. Annu. Rev. Cell Dev. Biol. 11, 73–91 (1995).

14 Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature 407(6801), 249–257 (2000).

15 Folkman J, Cole P, Zimmerman S. Tumor behavior in isolated perfused organs: in vitro growth and metastases of biopsy material in rabbit thyroid and canine intestinal segment. Ann. Surg. 164(3), 491–502 (1966).

16 Folkman J. What is the evidence that tumors are angiogenesis dependent? J. Natl Cancer Inst. 82(1), 4–6 (1990).

17 Folkman J. Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 285(21), 1182–1186 (1971).

•• Discussestheinitialconceptofangiogenicblockingasanti-cancertherapy.

18 Holash J, Maisonpierre PC, Compton D et al. Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 284(5422), 1994–1998 (1999).

•• Gooddiscussionontheconceptofvesselco-option.

19 Leenders WP, Kusters B, de Waal RM. Vessel co-option: how tumors obtain blood supply in the absence of sprouting angiogenesis. Endothelium 9(2), 83–87 (2002).

20 Zagzag D, Amirnovin R, Greco MA et al. Vascular apoptosis and involution in gliomas precede neovascularization: a novel concept for glioma growth and angiogenesis. Lab. Invest. 80(6), 837–849 (2000).

21 Kargiotis O, Rao JS, Kyritsis AP. Mechanisms of angiogenesis in gliomas. J. Neurooncol. 78(3), 281–293 (2006).


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Mic

higa

n U

nive

rsity

on

11/0

6/14

For

pers

onal

use

onl

y.


Review

22 Folkman J. Angiogenesis: initiation and control. Ann. N. Y. Acad. Sci. 401, 212–227 (1982).

23 Folkman J. Tumor angiogenesis. Adv. Cancer Res. 43, 175–203 (1985).

24 Folkman J. How is blood vessel growth regulated in normal and neoplastic tissue? G.H.A. Clowes memorial Award lecture. Cancer Res. 46(2), 467–473 (1986).

25 Jain RK, Tong RT, Munn LL. Effect of vascular normalization by antiangiogenic therapy on interstitial hypertension, peritumor edema, and lymphatic metastasis: insights from a mathematical model. Cancer Res. 67(6), 2729–2735 (2007).

26 Fukumura D, Xu L, Chen Y, Gohongi T, Seed B, Jain RK. Hypoxia and acidosis independently up-regulate vascular endothelial growth factor transcription in brain tumors in vivo. Cancer Res. 61(16), 6020–6024 (2001).

27 Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat. Med. 9(6), 669–676 (2003).

•• GooddiscussiononVEGF.

28 Herold-Mende C, Steiner HH, Andl T et al. Expression and functional significance of vascular endothelial growth factor receptors in human tumor cells. Lab. Invest. 79(12), 1573–1582 (1999).

29 Rahimi N, Dayanir V, Lashkari K. Receptor chimeras indicate that the vascular endothelial growth factor receptor-1 (VEGFR-1) modulates mitogenic activity of VEGFR-2 in endothelial cells. J. Biol. Chem. 275(22), 16986–16992 (2000).

30 Ellis LM. The role of neuropilins in cancer. Mol. Cancer Ther. 5, 1099–1107 (2006).

31 Takano S, Yoshii Y, Kondo S et al. Concentration of vascular endothelial growth factor in the serum and tumor tissue of brain tumor patients. Cancer Res. 56(9), 2185–2190 (1996).

32 Schmidt N, Westphal M, Hagel C. Levels of vascular endothelial growth factor, hepatocyte growth factor/scatter factor and basic fibroblast growth factor in human gliomas and their relation to angiogenesis. Int. J. Cancer 84, 10–18 (1999).

33 Ding H, Roncari L, Wu X et al. Expression and hypoxic regulation of angiopoietins in human astrocytomas. Neuro-oncology 3(1), 1–10 (2001).

34 Samoto K, Ikezaki K, Ono M et al. Expression of vascular endothelial growth factor and its possible relation with neovascularization in human brain tumors. Cancer Res. 55(5), 1189–1193 (1995).

35 Peters BA, Diaz LA, Polyak K et al. Contribution of bone marrow-derived endothelial cells to human tumor vasculature. Nat. Med. 11(3), 261–262 (2005).

36 Kim I, Kim HG, So JN, Kim JH, Kwak HJ, Koh GY. Angiopoietin-1 regulates endothelial cell survival through the phosphatidylinositol 3’-kinase/Akt signal transduction pathway. Circ. Res. 86(1), 24–29 (2000).

37 Maisonpierre PC, Suri C, Jones PF et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277(5322), 55–60 (1997).

38 Yoshiji H, Kuriyama S, Yoshii J et al. Synergistic effect of basic fibroblast growth factor and vascular endothelial growth factor in murine hepatocellular carcinoma. Hepatology 35(4), 834–842 (2002).

39 Mandriota SJ, Pepper MS. Vascular endothelial growth factor-induced in vitro angiogenesis and plasminogen activator expression are dependent on endogenous basic fibroblast growth factor. J. Cell. Sci. 110(Pt 18), 2293–2302 (1997).

40 Guo P, Hu B, Gu W et al. Platelet-derived growth factor-B enhances glioma angiogenesis by stimulating vascular endothelial growth factor expression in tumor endothelia and by promoting pericyte recruitment. Am. J. Pathol. 162(4), 1083–1093 (2003).

41 Wang D, Huang HJ, Kazlauskas A, Cavenee WK. Induction of vascular endothelial growth factor expression in endothelial cells by platelet-derived growth factor through the activation of phosphatidylinositol 3-kinase. Cancer Res. 59(7), 1464–1472 (1999).

42 Dunn IF, Heese O, Black PM. Growth factors in glioma angiogenesis: FGFs, PDGF, EGF, and TGFs. J. Neurooncol. 50(1–2), 121–137 (2000).

43 Koochekpour S, Merzak A, Pilkington GJ. Vascular endothelial growth factor production is stimulated by gangliosides and TGF-beta isoforms in human glioma cells in vitro. Cancer Lett. 102(1-2), 209–215 (1996).

44 Platten M, Wick W, Weller M. High-grade glioma biology: role for TGF-beta in growth, motility, angiogenesis, and immune escape. Microsc. Res. Tech. 52(4), 401–410 (2001).

45 Platten M, Wick W, Wild-Bode C, Aulwurm S, Dichgans J, Weller M. Transforming growth factors beta(1) (TGF-beta(1)) and TGF-beta(2) promote

glioma cell migration via Up-regulation of alpha(V)beta(3) integrin expression. Biochem. Biophys. Res. Commun. 268(2), 607–611 (2000).

46 Kunkel P, Müller S, Schirmacher P et al. Expression and localization of scatter factor/hepatocyte growth factor in human astrocytomas. Neuro-oncology 3(2), 82–88 (2001).

47 Loeffler S, Fayard B, Weis J, Weissenberger J. Interleukin-6 induces transcriptional activation of vascular endothelial growth factor (VEGF) in astrocytes in vivo and regulates VEGF promoter activity in glioblastoma cells via direct interaction between STAT3 and Sp1. Int. J. Cancer 115(2), 202–213 (2005).

48 Wakabayashi Y, Shono T, Isono M et al. Dual pathways of tubular morphogenesis of vascular endothelial cells by human glioma cells: vascular endothelial growth factor/basic fibroblast growth factor and interleukin-8. Jpn. J. Cancer Res. 86(12), 1189–1197 (1995).

49 Rolhion C, Penault-Llorca F, Kémény JL et al. Interleukin-6 overexpression as a marker of malignancy in human gliomas. J. Neurosurg. 94(1), 97–101 (2001).

50 Maruno M, Kovach JS, Kelly PJ, Yanagihara T. Distribution of endogenous tumour necrosis factor alpha in gliomas. J. Clin. Pathol. 50(7), 559–562 (1997).

51 Roessler K, Suchanek G, Breitschopf H et al. Detection of tumor necrosis factor-alpha protein and messenger RNA in human glial brain tumors: comparison of immunohistochemistry with in situ hybridization using molecular probes. J. Neurosurg. 83(2), 291–297 (1995).

52 Chambaut-Guérin AM, Costa SL, Lefrançois T, Fages C, Gauthereau X, Tardy M. Effects of retinoic acid and tumor necrosis factor alpha on GL-15 glioblastoma cells. Neuroreport 11(2), 389–393 (2000).

53 Yoshida S, Ono M, Shono T et al. Involvement of interleukin-8, vascular endothelial growth factor, and basic fibroblast growth factor in tumor necrosis factor alpha-dependent angiogenesis. Mol. Cell. Biol. 17(7), 4015–4023 (1997).

54 Bello L, Francolini M, Marthyn P et al. Alpha(v)beta3 and alpha(v)beta5 integrin expression in glioma periphery. Neurosurgery 49(2), 380–389; discussion 390 (2001).

55 D’Abaco GM, Kaye AH. Integrins: molecular determinants of glioma invasion. J. Clin. Neurosci. 14(11), 1041–1048 (2007).

Jo, Schiff & Purow

Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Mic

higa

n U

nive

rsity

on

11/0

6/14

For

pers

onal

use

onl

y.


Review

56 Binder DK, Berger MS. Proteases and the biology of glioma invasion. J. Neurooncol. 56(2), 149–158 (2002).

57 Galli R, Binda E, Orfanelli U et al. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res. 64(19), 7011–7021 (2004).

58 Hemmati HD, Nakano I, Lazareff JA et al. Cancerous stem cells can arise from pediatric brain tumors. Proc. Natl. Acad. Sci. USA 100(25), 15178–15183 (2003).

59 Singh SK, Clarke ID, Terasaki M et al. Identification of a cancer stem cell in human brain tumors. Cancer Res. 63(18), 5821–5828 (2003).

60 Singh SK, Hawkins C, Clarke ID et al. Identification of human brain tumour initiating cells. Nature 432(7015), 396–401 (2004).

61 Bao S, Wu Q, McLendon RE et al. Stem cell-like glioma cells promote radioresistance by preferential activation of the DNA damage response. Nature 444, 756–760 (2006).

62 Calabrese C, Poppleton H, Kocak M et al. A perivascular niche for brain tumor stem cells. Cancer Cell 11(1), 69–82 (2007).

63 Folkins C, Shaked Y, Man S et al. Glioma tumor stem-like cells promote tumor angiogenesis and vasculogenesis via vascular endothelial growth factor and stromal-derived factor 1. Cancer Res. 69(18), 7243–7251 (2009).

64 Cheng L, Bao S, Rich JN. Potential therapeutic implications of cancer stem cells in glioblastoma. Biochem. Pharmacol. 80(5), 654–665 (2010).

65 Lathia JD, Hitomi M, Gallagher J et al. Distribution of CD133 reveals glioma stem cells self-renew through symmetric and asymmetric cell divisions. Cell Death Dis. 2, e200 (2011).

66 Garcia JL, Perez-Caro M, Gomez-Moreta JA et al. Molecular analysis of ex-vivo CD133+ GBM cells revealed a common invasive and angiogenic profile but different proliferative signatures among high grade gliomas. BMC Cancer 10, 454 (2010).

67 Kerbel RS. Antiangiogenic therapy: a universal chemosensitization strategy for cancer? Science 312(5777), 1171–1175 (2006).

• Gooddiscussiononmechanismsofantiangiogenicagentsthatmayexplainthechemosensitizingactivity.

68 Sathornsumetee S, Rich JN. Antiangiogenic therapy in high-grade glioma: promise and challenge. Curr. Pharm. Des. 13(35), 3545–3558 (2007).

• Goodreviewaboutantiangiogenictreatmentinhigh-gradegliomas.

69 Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307(5706), 58–62 (2005).

•• Seminalpaperonnormalizationoftumorvasculaturehypothesisanditsimplicationinclinicalpractice.

70 Jain RK, Duda DG, Clark JW, Loeffler JS. Lessons from Phase III clinical trials on anti-VEGF therapy for cancer. Nat. Clin. Pract. Oncol. 3(1), 24–40 (2006).

71 Gorski DH, Beckett MA, Jaskowiak NT et al. Blockage of the vascular endothelial growth factor stress response increases the antitumor effects of ionizing radiation. Cancer Res. 59(14), 3374–3378 (1999).

72 Shaked Y, Kerbel RS. Antiangiogenic strategies on defense: on the possibility of blocking rebounds by the tumor vasculature after chemotherapy. Cancer Res. 67(15), 7055–7058 (2007).

73 Browder T, Butterfield CE, Kräling BM et al. Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res. 60(7), 1878–1886 (2000).

74 Bertolini F, Paul S, Mancuso P et al. Maximum tolerable dose and low-dose metronomic chemotherapy have opposite effects on the mobilization and viability of circulating endothelial progenitor cells. Cancer Res. 63(15), 4342–4346 (2003).

75 Bao S, Wu Q, Sathornsumetee S et al. Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res. 66(16), 7843–7848 (2006).

76 Ferrara N, Hillan KJ, Gerber HP, Novotny W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat. Rev. Drug Discov. 3(5), 391–400 (2004).

77 Hurwitz H, Fehrenbacher L, Novotny W et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N. Engl. J. Med. 350(23), 2335–2342 (2004).

78 Stark Vance V. Bevacizumab and CPT-11 in the treatment of relapsed high-grade glioma. Neuro-Oncology 7, Abstract 342 (2005).

79 Pope WB, Lai A, Nghiemphu P, Mischel P, Cloughesy TF. MRI in patients with

high-grade gliomas treated with bevacizumab and chemotherapy. Neurology 66(8), 1258–1260 (2006).

80 Vredenburgh JJ, Desjardins A, Herndon JE 2nd et al. Phase II trial of bevacizumab and irinotecan in recurrent high-grade glioma. Clin. Cancer Res. 13(4), 1253–1259 (2007).

81 Macdonald DR, Cascino TL, Schold SC Jr, Cairncross JG. Response criteria for Phase II studies of supratentorial high-grade glioma. J. Clin. Oncol. 8(7), 1277–1280 (1990).

82 Vredenburgh JJ, Desjardins A, Herndon JE 2nd et al. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J. Clin. Oncol. 25(30), 4722–4729 (2007).

83 Desjardins A, Vredenburgh JJ, Reardon DA et al. Long-term survival from the initial trial of bevacizumab and irinotecan. J. Clin. Oncol. 28(Suppl. 15), Abstract 2045 (2010).

84 Vredenburgh JJ, Cloughesy T, Samant M et al. Corticosteroid use in patients with glioblastoma at first or second relapse treated with bevacizumab in the BRAIN study. Oncologist 15(12), 1329–1334 (2010).

85 Wefel JS, Cloughesy T, Zazzali JL et al. Neurocognitive function in patients with recurrent glioblastoma treated with bevacizumab. Neuro-oncology 13(6), 660–668 (2011).

86 Taillibert S, Vincent LA, Granger B et al. Bevacizumab and irinotecan for recurrent oligodendroglial tumors. Neurology 72(18), 1601–1606 (2009).

87 Reardon DA, Desjardins A, Vredenburgh JJ et al. Metronomic chemotherapy with daily, oral etoposide plus bevacizumab for recurrent high-grade glioma: a Phase II study. Br. J. Cancer 101(12), 1986–1994 (2009).

88 Chinot OL, de La Motte Rouge T, Moore N et al. Phase 3 trial of bevacizumab plus temozolomide and radiotherapy in newly diagnosed glioblastoma multiforme (ND-GBM) [abstract]. Neuro. Oncol. 11(5), 628 (2009).

89 Desjardins A, Reardon DA, Herndon JE 2nd et al. Bevacizumab plus irinotecan in recurrent WHO grade 3 high-grade gliomas. Clin. Cancer Res. 14(21), 7068–7073 (2008).

90 Kreisl TN, Zhang W, Odia Y et al. A Phase II trial of single-agent bevacizumab in patients with recurrent anaplastic glioma. Neuro-oncology 13(10), 1143–1150 (2011).

91 Francesconi AB, Dupre S, Matos M et al. Carboplatin and etoposide combined with bevacizumab for the treatment of recurrent


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Mic

higa

n U

nive

rsity

on

11/0

6/14

For

pers

onal

use

onl

y.


Review

glioblastoma multiforme. J. Clin. Neurosci. 17(8), 970–974 (2010).

92 Kang TY, Jin T, Elinzano H, Peereboom D. Irinotecan and bevacizumab in progressive primary brain tumors, an evaluation of efficacy and safety. J. Neurooncol. 89(1), 113–118 (2008).

93 Zuniga RM, Torcuator R, Jain R et al. Efficacy, safety and patterns of response and recurrence in patients with recurrent high-grade gliomas treated with bevacizumab plus irinotecan. J. Neurooncol. 91(3), 329–336 (2009).

94 Ali SA, McHayleh WM, Ahmad A et al. Bevacizumab and irinotecan therapy in glioblastoma multiforme: a series of 13 cases. J. Neurosurg. 109(2), 268–272 (2008).

95 Bokstein F, Shpigel S, Blumenthal DT. Treatment with bevacizumab and irinotecan for recurrent high-grade glial tumors. Cancer 112(10), 2267–2273 (2008).

96 Hasselbalch B, Lassen U, Hansen S et al. Cetuximab, bevacizumab, and irinotecan for patients with primary glioblastoma and progression after radiation therapy and temozolomide: a Phase II trial. Neuro-oncology 12(5), 508–516 (2010).

97 Nghiemphu PL, Liu W, Lee Y et al. Bevacizumab and chemotherapy for recurrent glioblastoma: a single-institution experience. Neurology 72(14), 1217–1222 (2009).

98 Norden AD, Young GS, Setayesh K et al. Bevacizumab for recurrent high-grade gliomas: efficacy, toxicity, and patterns of recurrence. Neurology 70(10), 779–787 (2008).

99 Sathornsumetee S, Desjardins A, Vredenburgh JJ et al. Phase II trial of bevacizumab and erlotinib in patients with recurrent high-grade glioma. Neuro-oncology 12(12), 1300–1310 (2010).

100 Gutin PH, Iwamoto FM, Beal K et al. Safety and efficacy of bevacizumab with hypofrationated stereotactic irradiation for recurrent high-grade gliomas. Int. J. Radiar. Oncol. Biol. Phys. 75(1), 156–163 (2009).

101 Mathieu V, De Nève N, Le Mercier M et al. Combining bevacizumab with temozolomide increases the antitumor efficacy of temozolomide in a human glioblastoma orthotopic xenograft model. Neoplasia 10(12), 1383–1392 (2008).

102 Holash J, Davis S, Papadopoulos N et al. VEGF-Trap: a VEGF blocker with potent

antitumor effects. Proc. Natl Acad. Sci. USA 99(17), 11393–11398 (2002).

103 Gomez-Manzano C, Holash J, Fueyo J et al. VEGF Trap induces antiglioma effect at different stages of disease. Neuro-oncology 10(6), 940–945 (2008).

104 de Groot JF, Lamborn KR, Chang SM et al. Phase II study of aflibercept in recurrent high-grade glioma: a North American Brain Tumor Consortium study. J. Clin. Oncol. 29(19), 2689–2695 (2011).

105 Wachsberger PR, Burd R, Cardi C et al. VEGF trap in combination with radiotherapy improves tumor control in u87 glioblastoma. Int. J. Radiat. Oncol. Biol. Phys. 67(5), 1526–1537 (2007).

106 Reardon DA, Desjardins A, Rich JN, Vredenburgh JJ. The emerging role of anti-angiogenic therapy for high-grade glioma. Curr. Treat. Options Oncol. 9(1), 1–22 (2008).

107 Brandsma D, van den Bent MJ. Molecular targeted therapies and chemotherapy in high-grade gliomas. Curr. Opin. Oncol. 19(6), 598–605 (2007).

• Seminalpaperonthenormalizationhypothesisanditsimplicationsinclinicalpractice.

108 Batchelor TT, Sorensen AG, di Tomaso E et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11(1), 83–95 (2007).

• Thefirststudytoidentifytheonsetanddurationofthevascularnormalizationtimewindowbyantiangiogenicagent.

109 Batchelor TT, Duda DG, di Tomaso E et al. Phase II study of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. J. Clin. Oncol. 28(17), 2817–2823 (2010).

110 Batchelor T, Mulholland P, Neyns B. The efficacy of cediranib as monotherapy and in combination with lomustine compared to lomustine alone in patients with recurrent glioblastoma: a Phase III randomized study. Neuro-Oncology, 12(Suppl. 4), iv69–iv78 (2010).

111 Neyns B, Sadones J, Chaskis C et al. Phase II study of sunitinib malate in patients with recurrent high-grade glioma. J. Neurooncol. 103(3), 491–501 (2011).

112 Iwamoto FM, Lamborn KR, Robins HI et al. Phase II trial of pazopanib (GW786034), an oral multi-targeted angiogenesis inhibitor, for adults with

recurrent glioblastoma (North American Brain Tumor Consortium Study 06-02). Neuro-oncology 12(8), 855–861 (2010).

113 de Groot JF, Prados M, Urquhart, T et al. A Phase II study of XL184 in patients with progressive glioblastoma multiforme (GBM) in first or second relapse. J. Clin. Oncol. 27(Suppl. 15), Abstract 2047 (2009).

114 Lacouture M, Lenihan D, Quaggin S. Targeting Tumor Angiogenesis. Antiangiogenic therapy: tolerability and management of side effects. The Angiogenesis Foundation (2009).

115 Armstrong TS, Wen PY, Gilbert MR, Schiff D et al. Management of treatment associated toxicities of anti-anigogenic therapy in patients with brain tumors. Neuro-Oncol doi:10.1093/neuonc/nor223 (2012) (Epub ahead of print).

•• Excellentdiscussiononantiangiogenictreatment-associatedtoxicities.

116 Kamba T, McDonald DM. Mechanisms of adverse effects of anti-VEGF therapy for cancer. Br. J. Cancer 96(12), 1788–1795 (2007).

117 Zhu X, Wu S, Dahut WL, Parikh CR. Risks of proteinuria and hypertension with bevacizumab, an antibody against vascular endothelial growth factor: systematic review and meta-analysis. Am. J. Kidney Dis. 49(2), 186–193 (2007).

118 Eremina V, Jefferson JA, Kowalewska J et al. VEGF inhibition and renal thrombotic microangiopathy. N. Engl. J. Med. 358(11), 1129–1136 (2008).

119 Levy CF, Oo KZ, Fireman F et al. Reversible posterior leukoencephalopathy syndrome in a child treated with bevacizumab. Pediatr. Blood Cancer 52(5), 669–671 (2009).

120 Scappaticci FA, Fehrenbacher L, Cartwright T et al. Surgical wound healing complications in metastatic colorectal cancer patients treated with bevacizumab. J. Surg. Oncol. 91(3), 173–180 (2005).

121 Shen Q, Goderie SK, Jin L et al. Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science 304(5675), 1338–1340 (2004).

122 Dietrich J, Han R, Yang Y, Mayer-Pröschel M, Noble M. CNS progenitor cells and oligodendrocytes are targets of chemotherapeutic agents in vitro and in vivo. J. Biol. 5(7), 22 (2006).

123 Bergers G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat. Rev. Cancer 8(8), 592–603 (2008).

Jo, Schiff & Purow

Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Mic

higa

n U

nive

rsity

on

11/0

6/14

For

pers

onal

use

onl

y.


Review

124 Du R, Lu KV, Petritsch C et al. HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell 13(3), 206–220 (2008).

125 Norden AD, Drappatz J, Wen PY. Antiangiogenic therapies for high-grade glioma. Nat. Rev. Neurol. 5(11), 610–620 (2009).

126 Ebos JM, Lee CR, Christensen JG, Mutsaers AJ, Kerbel RS. Multiple circulating proangiogenic factors induced by sunitinib malate are tumor-independent and correlate with antitumor efficacy. Proc. Natl Acad. Sci. USA 104(43), 17069–17074 (2007).

127 Erber R, Thurnher A, Katsen AD et al. Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms. FASEB J. 18(2), 338–340 (2004).

128 Motzer R, Escudier B, Oudard S et al.; RECORD-1 Study Group. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled Phase III trial. Lancet 372(9637), 449–456 (2008).

129 Jaeckle KA, Schiff D, Anderson SK et al. NCCTG N0572 Phase I/II trial of sorafenib and temsirolimus in patients with recurrent glioblastoma: a North Central Cancer Treatment Group study. J. Clin. Oncol. 29(Suppl.), Abstract 2033 (2011).

130 Blouw B, Song H, Tihan T et al. The hypoxic response of tumors is dependent on their microenvironment. Cancer Cell 4(2), 133–146 (2003).

131 Miletic H, Niclou SP, Johansson M, Bjerkvig R. Anti-VEGF therapies for high-grade glioma: treatment effects and escape mechanisms. Expert Opin. Ther. Targets 13(4), 455–468 (2009).

132 Keunen O, Johansson M, Oudin A et al. Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma. Proc. Natl Acad. Sci. USA 108(9), 3749–3754 (2011).

133 Iwamoto FM, Abrey LE, Beal K et al. Patterns of relapse and prognosis after bevacizumab failure in recurrent glioblastoma. Neurology 73(15), 1200–1206 (2009).

134 Fischer I, Cunliffe CH, Bollo RJ et al. High-grade glioma before and after treatment with radiation and Avastin:

initial observations. Neuro-oncology 10(5), 700–708 (2008).

135 Wick A, Dörner N, Schäfer N et al. Bevacizumab does not increase the risk of remote relapse in high-grade glioma. Ann. Neurol. 69(3), 586–592 (2011).

136 Pope WB, Xia Q, Paton VE et al. Patterns of progression in patients with recurrent glioblastoma treated with bevacizumab. Neurology 76(5), 432–437 (2011).

137 Wen PY, Macdonald DR, Reardon DA et al. Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J. Clin. Oncol. 28(11), 1963–1972 (2010).

138 Hylton N. Dynamic contrast-enhanced magnetic resonance imaging as an imaging biomarker. J. Clin. Oncol. 24(20), 3293–3298 (2006).

139 Sorensen AG, Batchelor TT, Zhang W-T et al. A ‘vascular normalization index’ as potential mechanistic biomarker to predict survival after a single dose of cediranib in recurrent glioblastoma patients. Cancer Res. 69, 5296–5300 (2009).

140 Jain R, Scarpace LM, Ellika S et al. Imaging response criteria for recurrent gliomas treated with bevacizumab: role of diffusion weighted imaging as an imaging biomarker. J. Neurooncol. 96(3), 423–431 (2010).

141 Gerstner ER, Chen PJ, Wen PY, Jain RK, Batchelor TT, Sorensen G. Infiltrative patterns of glioblastoma spread detected via diffusion MRI after treatment with cediranib. Neuro-oncology 12(5), 466–472 (2010).

142 Essock-Burns E, Lupo JM, Cha S et al. Assessment of perfusion MRI-derived parameters in evaluating and predicting response to antiangiogenic therapy in patients with newly diagnosed glioblastoma. Neuro-oncology 13(1), 119–131 (2011).

143 Chen W, Delaloye S, Silverman DH et al. Predicting treatment response of high-grade gliomas to bevacizumab and irinotecan by imaging proliferation with [18F] fluorothymidine positron emission tomography: a pilot study. J. Clin. Oncol. 25(30), 4714–4721 (2007).

144 Prados M, Cloughesy T, Samant M et al. Response as a predictor of survival in patients with recurrent glioblastoma treated with bevacizumab. Neuro-oncology 13(1), 143–151 (2011).

145 Sathornsumetee S, Cao Y, Marcello JE et al. Tumor angiogenic and hypoxic profiles predict radiographic response and survival in malignant astrocytoma patients treated with bevacizumab and irinotecan. J. Clin. Oncol. 26(2), 271–278 (2008).

146 Hasselbalch B, Eriksen JG, Broholm H et al. Prospective evaluation of angiogenic, hypoxic and EGFR-related biomarkers in recurrent glioblastoma multiforme treated with cetuximab, bevacizumab and irinotecan. APMIS 118(8), 585–594 (2010).

147 de Groot JF, Piao Y, Tran H et al. Myeloid biomarkers associated with glioblastoma response to anti-VEGF therapy with aflibercept. Clin. Cancer Res. 17(14), 4872–4881 (2011).

148 Olson RA, Brastianos PK, Palma DA. Prognostic and predictive value of epigenetic silencing of MGMT in patients with high grade gliomas: a systematic review and meta-analysis. J. Neurooncol. 105(2), 325–335 (2011).

149 Pallini R, Ricci-Vitiani L, Montano N et al. Expression of the stem cell marker CD133 in recurrent glioblastoma and its value for prognosis. Cancer 117(1), 162–174 (2011).

150 Zhou Q, Gallo JM. Differential effect of sunitinib on the distribution of temozolomide in an orthotopic glioma model. Neuro-oncology 11(3), 301–310 (2009).

151 de Groot JF. High-dose antiangiogenic therapy for glioblastoma: less may be more? Clin. Cancer Res. 17(19), 6109–6111 (2011).

Websites

201 ClinicalTrials.gov. Aflibercept, Radiation Therapy, and Temozolomide in Treating Patients With Newly Diagnosed or Recurrent Glioblastoma Multiforme, Gliosarcoma, or Other Malignant Glioma. www.clinicaltrials.gov/ct2/show/NCT00650923

202 ClinicalTrials.gov. http://clinicaltrials.gov

203 Bhatt RS, Atkins MB. Translational research studies in renal cancer: mechanisms and management of resistance to anti-VEGF therapy in renal cell carcinoma. www.informedicalcme.com/renal/vegf- pathway-resistance-in-renal-cell-carcinoma


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Mic

higa

n U

nive

rsity

on

11/0

6/14

For

pers

onal

use

onl

y.

angiogenic inhibition in high-grade gliomas: past, present and future

Documents