CNS Oncology
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Antiangiogenic therapies for glioblastoma Isabel Arrillaga-Romany1 & Andrew D Norden*,2 Practice points ●● Glioblastoma (GBM) is the most common malignant primary brain tumor in adults and remains incurable.
●● Median overall survival is roughly 15 months with standard of care treatment, which includes 6 weeks of concurrent radiation and temozolomide followed by 6–12 months of adjuvant temozolomide.
●● Early Phase II trials of bevacizumab in recurrent GBM provided evidence of clinical benefit and served as the impetus for the accelerated US FDA approval of bevacizumab in 2009.
●● Two recent Phase III randomized trials of antiangiogenic therapy at initial diagnosis suggested improvement in progression-free survival, but failed to show an overall survival benefit.
●● Antiedema effects of antiangiogenic therapy with concomitant decrease in corticosteroid dependency were reported.
●● Resistance mechanisms are under active investigation and may help to improve overall efficacy of antiangiogenic agents.
Summary Glioblastoma is the most prevalent malignant primary brain tumor in adults and to date effective durable treatments are lacking. Preclinical studies underscore the importance of neovascularization for tumor survival, making angiogenesis an important treatment target. Early clinical experience in recurrent glioblastoma suggested that antiangiogenic agents may provide clinical benefit by prolonging progression-free survival, improving quality of life and decreasing peritumoral edema. Two recent Phase III randomized trials of antiangiogenic therapy at initial diagnosis suggested improvement in progressionfree survival, but failed to show an overall survival benefit. Ongoing preclinical research focuses on mechanisms of resistance and potential predictive biomarkers. Identification of targets to resistance pathways and of predictive biomarkers will hopefully improve efficacy of antiangiogenic therapies.
Keywords
• antiangiogenesis • bevacizumab • glioblastoma • proangiogenic factors • resistance mechanisms • small-molecule inhibitor • vascular endothelial growth factor • VEGF
Background Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and remains incurable. Median overall survival is roughly 15 months with standard of care treatment, which includes 6 weeks of concurrent radiation and temozolomide followed by 6–12 months of adjuvant temozolomide [1] . GBM is a highly vascularized tumor in which microvascular proliferation is typically observed. The precise mechanism by which angiogenesis impacts tumor growth and survival remains in question. VEGF has been identified as a prominent mediator of tumor angiogenesis [2–4] making interference with VEGF signaling a focus of significant scientific interest. Other antiangiogenic treatment strategies remain under active investigation. In this chapter Stephen E & Catherine Pappas Center for Neuro-Oncology, Massachusetts General Hospital, Boston, MA, USA Center for Neuro-Oncology, Dana-Farber/Brigham & Women’s Cancer Center, 450 Brookline Avenue, Boston, MA 02215, USA *Author for correspondence: Tel.: +1 617 632 2166; Fax: +1 617 632 4773; [email protected] 1 2
10.2217/CNS.14.31 © 2014 Future Medicine Ltd
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Review Arrillaga-Romany & Norden we will review basic mechanisms, evidence of efficacy and potential benefits of treatment with antiangiogenic therapy. Angiogenesis mechanisms The precise mechanism by which antiangiogenic therapy impacts GBM is uncertain. Classically, angiogenesis was thought to enhance tumorigenesis by increasing delivery of nutrients, oxygen and other growth factors necessary for tumor survival [5] . Blockade of new vessel formation would thereby limit access to these same elements. Early preclinical work indeed supported the role of vascular proliferation in tumor survival and propagation [6,7] . Alternative theories propose that antiangiogenesis works by promoting the ‘normalization’ of tumor vasculature. Tumor blood vessels are plentiful but aberrant in organization, architecture and physiology [8] , thus limiting delivery of chemotherapy agents and oxygen required for radiation to achieve antitumor effects. Tumor vessels are often hyperpermeable with enlarged diameters, thickened basement membranes and a reduced number of associated perivascular cells. These abnormalities elevate interstitial pressures and result in increased peritumoral edema. They diminish vascular perfusion leading to tumor hypoxia. By normalizing the vasculature, antiangiogenic therapy may improve perfusion, oxygenation, delivery of chemotherapy agents [8] and peritumoral edema [9] . This ability of antiangiogenic therapy to normalize tumor vasculature as measured using various imaging parameters has been linked to its efficacy [10–12] . Antiangiogenic targets The complex nature of the angiogenic process in cancer provides numerous targets for therapy. VEGF is the most thoroughly investigated proangiogenic factor in GBM and is likely the central mediator of neovascularization in many tumors [13,14] . Levels of VEGF receptor (VEGFR) ligand correlate with grade of glioma [15] , with mean concentrations of VEGF being 11-fold higher in extracts from grade III and IV gliomas than in extracts from lower grade counterparts. Preclinical work confirms that blockade of VEGF inhibits new tumor vessel formation and halts malignant glioma progression. Members of the VEGF family include VEGF-B, VEGF-C, VEGF-D and PIGF, but VEGF-A has the best established role in pathologic angiogenesis [16] .
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Three VEGFR subtypes have been identified. VEGFR-1 and VEGFR-2 are essential for the normal development of the vasculature, and their inhibition during embryogenesis is lethal [17] . VEGF-A binds to VEGFR-2 on endothelial cells to promote endothelial cell growth and survival through paracrine signaling pathways [18] . The role of VEGFR-1 is less well defined, but does not appear to directly involve tumor angiogenesis. VEGFR-1 may, however, indirectly influence tumor survival by recruitment of bone marrow-derived cells that can differentiate into cells that promote the structure and integrity of new vasculature [19,20] . VEGFR-3 regulates lymphangiogenesis [21] . The identification of VEGF as an essential regulator of angiogenesis led to the development of VEGF and VEGFR inhibitors. Several antibodies and receptor tyrosine kinase inhibitors (TKI) have been developed and tested against GBM in both clinical and preclinical settings. Antibodies have the benefit of high affinity and selectivity, although their size precludes their ability to cross the blood–brain barrier (BBB). This has been proposed as a potential limitation of antibodies in the treatment of primary brain tumors, although tumor-associated BBB disruption may allow for adequate infiltration of these agents into the tumor. Small-molecule TKIs have the advantage of easy penetration across the BBB, but less selectivity. TKIs also have the advantage of oral bioavailability while antibodies are administered intravenously. Bevacizumab, the recombinant monoclonal anti-VEGF antibody, was first humanized in 1997 from a murine prototype [20] . It binds to all subtypes of VEGF with high affinity and selectivity. In animal models, bevacizumab inhibits angiogenesis and halts tumor growth [22] , including GBM proliferation [3,23] . Early clinical experience with bevacizumab in advanced colon, breast and lung cancers paved the way for it to become the most commonly used and thoroughly investigated antiangiogenic agent for the treatment of high-grade gliomas [24] . Several other proangiogenic molecules have been implicated in tumor angiogenesis and remain under active investigation. Among them are FGF, SDF-1α, angiopoietins, PDGF, IL-8, HIF-1α, neuropilins, endoglins and hepatocyte growth factor, among others [2,15,25–32] . Some, such as angiopoetins [33] and neuropilins [34] , interact directly with receptors on endothelial cells to promote new vessel growth and survival,
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Antiangiogenic therapies for glioblastoma while others, such as SDF-1α, work indirectly by attracting proangiogenic bone marrow-derived cells [35,36] . Integrins are cell adhesion receptors that help regulate the vascular extracellular matrix and can influence angiogenesis [37] , representing a separate target with therapeutic potential for GBM. Expressivity of the αvβ3 and αvβ5 integrin heterodimer subtypes found on the tumor’s growing edge directly correlates with glioma grade [38] , suggesting a central role in tumorigenesis. Integrins are found on glioma endothelial cells and during angiogenesis are required for endothelial cell migration and proliferation [17,39] . They may also play a role in preventing apoptosis [40] , thereby supporting endothelial cell survival [39] . Efficacy of antiangiogenic therapy ●●Bevacizumab
Early Phase II trials of bevacizumab in recurrent GBM provided evidence of clinical benefit and served as the impetus for the accelerated US FDA approval of bevacizumab in 2009. The BRAIN trial was a randomized Phase II noncomparative trial evaluating the efficacy of bevacizumab monotherapy and bevacizumab plus irinotecan in 167 patients with recurrent GBM [41] . The progression-free survival at 6 months (PFS6) was 42.6 and 50.3% for monotherapy and combination therapy, respectively, which represented a marked improvement over historical controls. For patients with a radiographic response or PFS >6 months, neurocognitive function at 24 weeks relative to baseline was improved or remained stable [42] . Importantly, bevacizumab proved to be well tolerated in these early clinical trials. In the BR AIN trial, 46% of patients treated with bevacizumab alone experienced grade 3 adverse events, the most common of which were hypertension and seizure. More serious adverse events included intracranial hemorrhage, seen in 2.4% of patients in the bevacizumab-only group and in 3.4% of patients in the combination therapy group [41] . Two additional trials provided further support for the utility of bevacizumab in the recurrent GBM setting. The first of these was performed at the National Cancer Institute and evaluated bevacizumab monotherapy in 47 patients with recurrent GBM. PFS6 and radiographic response rates were 29 and 35%, respectively [43] . The second trial – BELOB, a Phase II randomized
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study with assumed little crossover – evaluated the efficacy of bevacizumab, lomustine, and combination of the two agents. Combination treatment yielded an overall survival (OS) benefit at 9 months compared to treatment with either of the agents alone (59% for combination treatment, 42% for lomustine only, and 38% for bevacizumab only) [44] . Two larger, randomized, multicenter, Phase III trials, AVAglio and RTOG 0825, were conducted in newly diagnosed GBM and found a benefit in PFS but not OS. In both studies, patients were treated with standard therapy combined with bevacizumab or placebo. In the RTOG 0825 trial, PFS results favored bevacizumab (bevacizumab: 10.7 months vs placebo: 7.3 months; HR: 0.79; p = 0.007), but did not reach the prespecified thresholds of HR: 0.7 and p = 0.004 [45] . Importantly, criteria for enrollment into the RTOG 0825 trial specified a minimal amount of resected tissue rendering patients who received biopsies ineligible. Some would argue that this requirement excluded the subgroup of patients who might benefit the most from treatment with bevacizumab. In the AVAglio trial, the addition of bevacizumab to standard therapy during the initial 6-week period of chemoradiation produced a clinically meaningful and statistically significant improvement in PFS (6.2 months for the control arm vs 10.6 months for the bevacizumab arm; HR: 0.64; p 50% of those patients were able to decrease corticosteroids by an average of 59% [66] . More recent Phase III trials confirm antiedema effects of bevacizumab with 66% of patients initially on corticosteroids able to discontinue their use after treatment with bevacizumab, versus 44% in the control arm [63] . Several other trials reported corticosteroid reductions in 33–59% of patients with recurrent GBM following bevacizumab treatment [43,67–69] . Preclinical studies further highlight the potent effects of antiangiogenic therapy on peritumoral edema [9] . In three different orthotopic murine glioma models, cediranib significantly alleviated edema through normalization of tumor vasculature. Additionally, cediranib prolonged survival without concomitant effects on tumor [9] , suggesting that the survival benefits of cediranib may be attributable, at least in part, to its antiedema effect. Resistance mechanisms In the hopes of improving efficacy, significant efforts have been devoted to the study of mechanisms underlying resistance to treatment with bevacizumab and other antiangiogeneic agents. Resistance in this setting can be thought of as either intrinsic or acquired, although mechanisms underlying both may overlap [70] . Intrinsic resistance refers to the inherent ability of glioma tumor cells to elude antiangiogenic therapy. Clinical and preclinical evidence suggests that a significant minority of high-grade gliomas might be refractory to VEGF-targeted therapy from treatment onset. For example, treatment with cediranib in a xenograft model of GBM did not affect tumor growth [9] and some patients respond minimally or not at all to treatment with VEGF inhibitors [11,71] . Inherent resistance may stem from redundant proangiogenic signaling pathways or from the existence of a pool of glioma stem cells that reside in a quiescent state unresponsive to antiangiogenic therapy [72,73] . After initial failed treatment with bevacizumab, use of a second-line bevacizumab containing regimen is typically ineffective. In this setting, PFS and response rates are extremely poor, supporting the notion of acquired resistance to antiangiogenic therapy [74] . Modes of acquired resistance under investigation include [72] :
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Table 1. Recent selected trials of antiangiogenic therapy for glioblastoma. Study, year (trial)
n
Design
Regimens
Friedman et al., 2009 (BRAIN)
167
Phase II randomized in rGBM
Kreisl et al., 2009 (NCI) Field et al., (CABARET)
67
Phase II prospective in rGBM
122
Phase II randomized in rGBM
Taal et al., 2013 (BELOB)
148
Phase II randomized in rGBM
Wick et al., 2013 (AvaGlio)
921
Phase III randomized in nGBM
Gilbert et al., 2013 (RTOG 0825)
637
Phase III randomized in nGBM
Batchelor et al., 2013 (REGAL)
325
Phase III randomized in rGBM
Stupp et al., 2013 (CENTRIC)
545
Phase III randomized in rGBM with methylated MGMT
PFS
OS
Median 6 months (months) (%)
Median (months)
9 months (%)
Bev alone Bev + IRI Bev alone
NA NA 4
42.6 50.3 29
10 9.5 7.8
NA NA NA
Bev alone Bev + carboplatin Bev alone Lomustine alone Bev + lomustine RT/TMZ + TMZ/Plc XRT/TMZ + TMZ/Bev RT/TMZ + TMZ/Plc XRT/TMZ + TMZ/Bev Cediranib alone Lomustine alone Cediranib + lomustine RT/TMX + TMZ/CIL TMZ/RT + TMZ/Plc
NA NA 3 2 4 6.2 10 7.3 10.7 3.1 4 2.5 13.5 10
24 26 18 11 41 NA NA NA NA NA NA NA NA NA
NA NA 38 43 59 NA NA NA NA NA NA NA NA NA
6.4 6 NA NA NA 16.8 16.9 16.1 15.7 8 9.4 9.8 26.3 26.3
Ref.
[41] [43] [62] [44]
[63] [64] [65]
[60]
Bev: Bevacizumab; CIL: Cilengitide; IRI: Irinotecan; MGMT: O6-methylguanine-DNA methyltransferase; NA: Not applicable; nGBM: Newly diagnosed glioblastoma; OS: Overall survival; PFS: Progression-free survival; Plc: Placebo; rGBM: Recurrent glioblastoma; RT: Radiation therapy; TMZ: Temozolamide.
●● Adaptive upregulation of proangiogenic
signaling pathways; ●● Recruitment of bone marrow derived
proangiogenic cells to the tumor site; ●● Transformation to a more invasive glioma
phenotype; ●● Promotion of autophagy.
Growth factors with increased expression during periods of resistance to anti-VEGF therapy include FGF-1, FGF-2, Ephrin-A1 (Eph-A1), Eph-A2, angiopoietin-1, VEGF, PlGF, granulocyte colony-stimulating factor, SDF-1α, stem-cell factor, signal transducer and activator of transcription 3 (STAT3) and osteopontin [11,75–78] . Release of these angiogenic factors can be induced by hypoxia, which itself may be provoked by excessive vessel pruning in the setting of angiogenesis inhibition. The upregulation of proangiogenic factors in response to anti-VEGF therapy may have additional clinical implications in that discontinuation of the treatment could result in accelerated tumor growth [70] . Bone marrow-derived proangiogenic cells have also been implicated in acquired resistance to antiangiogenic therapy [28,72,79] . These include tumor-activated macrophages, granulocytes and
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precursor myeloid cells, all of which are recruited to the tumor site in large quantities during resistance and tumor progression [9,80,81] . These cells stimulate the expression of cytokines, growth factors and proteases which may help to promote tumor growth. Precursor myeloid cells, including endothelial and pericyte progenitors, support angiogenesis and neovascularization by differentiating into cells that are essential to the structure and integrity of new vasculature [82,83] . Recruitment of myeloid precursor cells may be associated with the activation of p-STAT3, an important signaling molecule. AZD1480 is an inhibitor of the JAK/STAT pathway that has been used in combination with anti-VEGF TKI treatment in xenograft models of GBM. The combination reduced the influx of proangiogenic macrophages to the tumor site and improved survival [78,84] . Antiangiogenic therapy may also promote resistance by encouraging transformation to a more invasive and mesenchymal glioma phenotype [85,86] . This transformation is likely stimulated by an increase in tumor hypoxia through the upregulation of c-Met expression [87] . In preclinical models, cabozantinib (XL184), a co-inhibitor of c-MET and VEGF-R, amplifies the antiangiogenic phenomena and halts tumor growth
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B
C
D
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Figure 1. Effects of bevacizumab on tumor-associated vasogenic edema and contrast-enhancing tumor progression in glioblastoma multiforme (facing page). T2/FLAIR imaging obtained (A) immediately prior to and (B) 4 months after initiation of bevacizumab. Post-contrast T1 imaging obtained (C) immediately prior to and (D) 4 months after initiation of bevacizumab.
over blockade of VEGF-R alone [88] . Preliminary Phase II trial results of this agent revealed some efficacy in recurrent GBM [89] , but final results are pending. Onartuzamab, an antibody that inhibits MET, is currently in a Phase II clinical trial as combination therapy with bevacizumab for GBM. Predictive biomarkers Investigations into antiangiogenic therapy resistance mechanisms have gone hand-in-hand with efforts to identify biomarkers of response. Notable candidates have included imaging and serum markers of vascular normalization, which together can be viewed as the ‘vascular normalization index’. In a prospective Phase II trial of recurrent GBM, one dose of cediranib decreased tumor permeability on MRI in the subset of patients who achieved response to therapy and increased overall survival. No survival benefit was observed in patients whose initial permeability imaging was unaffected by treatment [11] . Likewise, in a subset of newly diagnosed GBM patients, the addition of cediranib to standard of care treatment with radiation and temozolomide increased vascular perfusion on MRI. This change in perfusion was evident early in treatment and was associated with an improvement in overall survival, suggesting that early imaging-based response may serve as a predictive biomarker for antiangiogenic therapy [10] . Circulating biomarkers of response may also exist. For example, the level of serum collagen IV (thought to reflect vessel basement membrane thinning) following one dose of cediranib has been associated with a survival benefit [12] . Although important and suggestive, biomarker data remain to be validated in randomized clinical trials. Conclusion & future perspective GBM remains a lethal neoplasm with no effective long-term treatment. The discovery of References 1
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Antiangiogenic therapies for glioblastoma Isabel Arrillaga-Romany1 & Andrew D Norden*,2 Practice points ●● Glioblastoma (GBM) is the most common malignant primary brain tumor in adults and remains incurable.
●● Median overall survival is roughly 15 months with standard of care treatment, which includes 6 weeks of concurrent radiation and temozolomide followed by 6–12 months of adjuvant temozolomide.
●● Early Phase II trials of bevacizumab in recurrent GBM provided evidence of clinical benefit and served as the impetus for the accelerated US FDA approval of bevacizumab in 2009.
●● Two recent Phase III randomized trials of antiangiogenic therapy at initial diagnosis suggested improvement in progression-free survival, but failed to show an overall survival benefit.
●● Antiedema effects of antiangiogenic therapy with concomitant decrease in corticosteroid dependency were reported.
●● Resistance mechanisms are under active investigation and may help to improve overall efficacy of antiangiogenic agents.
Summary Glioblastoma is the most prevalent malignant primary brain tumor in adults and to date effective durable treatments are lacking. Preclinical studies underscore the importance of neovascularization for tumor survival, making angiogenesis an important treatment target. Early clinical experience in recurrent glioblastoma suggested that antiangiogenic agents may provide clinical benefit by prolonging progression-free survival, improving quality of life and decreasing peritumoral edema. Two recent Phase III randomized trials of antiangiogenic therapy at initial diagnosis suggested improvement in progressionfree survival, but failed to show an overall survival benefit. Ongoing preclinical research focuses on mechanisms of resistance and potential predictive biomarkers. Identification of targets to resistance pathways and of predictive biomarkers will hopefully improve efficacy of antiangiogenic therapies.
Keywords
• antiangiogenesis • bevacizumab • glioblastoma • proangiogenic factors • resistance mechanisms • small-molecule inhibitor • vascular endothelial growth factor • VEGF
Background Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and remains incurable. Median overall survival is roughly 15 months with standard of care treatment, which includes 6 weeks of concurrent radiation and temozolomide followed by 6–12 months of adjuvant temozolomide [1] . GBM is a highly vascularized tumor in which microvascular proliferation is typically observed. The precise mechanism by which angiogenesis impacts tumor growth and survival remains in question. VEGF has been identified as a prominent mediator of tumor angiogenesis [2–4] making interference with VEGF signaling a focus of significant scientific interest. Other antiangiogenic treatment strategies remain under active investigation. In this chapter Stephen E & Catherine Pappas Center for Neuro-Oncology, Massachusetts General Hospital, Boston, MA, USA Center for Neuro-Oncology, Dana-Farber/Brigham & Women’s Cancer Center, 450 Brookline Avenue, Boston, MA 02215, USA *Author for correspondence: Tel.: +1 617 632 2166; Fax: +1 617 632 4773; [email protected] 1 2
10.2217/CNS.14.31 © 2014 Future Medicine Ltd
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Review Arrillaga-Romany & Norden we will review basic mechanisms, evidence of efficacy and potential benefits of treatment with antiangiogenic therapy. Angiogenesis mechanisms The precise mechanism by which antiangiogenic therapy impacts GBM is uncertain. Classically, angiogenesis was thought to enhance tumorigenesis by increasing delivery of nutrients, oxygen and other growth factors necessary for tumor survival [5] . Blockade of new vessel formation would thereby limit access to these same elements. Early preclinical work indeed supported the role of vascular proliferation in tumor survival and propagation [6,7] . Alternative theories propose that antiangiogenesis works by promoting the ‘normalization’ of tumor vasculature. Tumor blood vessels are plentiful but aberrant in organization, architecture and physiology [8] , thus limiting delivery of chemotherapy agents and oxygen required for radiation to achieve antitumor effects. Tumor vessels are often hyperpermeable with enlarged diameters, thickened basement membranes and a reduced number of associated perivascular cells. These abnormalities elevate interstitial pressures and result in increased peritumoral edema. They diminish vascular perfusion leading to tumor hypoxia. By normalizing the vasculature, antiangiogenic therapy may improve perfusion, oxygenation, delivery of chemotherapy agents [8] and peritumoral edema [9] . This ability of antiangiogenic therapy to normalize tumor vasculature as measured using various imaging parameters has been linked to its efficacy [10–12] . Antiangiogenic targets The complex nature of the angiogenic process in cancer provides numerous targets for therapy. VEGF is the most thoroughly investigated proangiogenic factor in GBM and is likely the central mediator of neovascularization in many tumors [13,14] . Levels of VEGF receptor (VEGFR) ligand correlate with grade of glioma [15] , with mean concentrations of VEGF being 11-fold higher in extracts from grade III and IV gliomas than in extracts from lower grade counterparts. Preclinical work confirms that blockade of VEGF inhibits new tumor vessel formation and halts malignant glioma progression. Members of the VEGF family include VEGF-B, VEGF-C, VEGF-D and PIGF, but VEGF-A has the best established role in pathologic angiogenesis [16] .
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Three VEGFR subtypes have been identified. VEGFR-1 and VEGFR-2 are essential for the normal development of the vasculature, and their inhibition during embryogenesis is lethal [17] . VEGF-A binds to VEGFR-2 on endothelial cells to promote endothelial cell growth and survival through paracrine signaling pathways [18] . The role of VEGFR-1 is less well defined, but does not appear to directly involve tumor angiogenesis. VEGFR-1 may, however, indirectly influence tumor survival by recruitment of bone marrow-derived cells that can differentiate into cells that promote the structure and integrity of new vasculature [19,20] . VEGFR-3 regulates lymphangiogenesis [21] . The identification of VEGF as an essential regulator of angiogenesis led to the development of VEGF and VEGFR inhibitors. Several antibodies and receptor tyrosine kinase inhibitors (TKI) have been developed and tested against GBM in both clinical and preclinical settings. Antibodies have the benefit of high affinity and selectivity, although their size precludes their ability to cross the blood–brain barrier (BBB). This has been proposed as a potential limitation of antibodies in the treatment of primary brain tumors, although tumor-associated BBB disruption may allow for adequate infiltration of these agents into the tumor. Small-molecule TKIs have the advantage of easy penetration across the BBB, but less selectivity. TKIs also have the advantage of oral bioavailability while antibodies are administered intravenously. Bevacizumab, the recombinant monoclonal anti-VEGF antibody, was first humanized in 1997 from a murine prototype [20] . It binds to all subtypes of VEGF with high affinity and selectivity. In animal models, bevacizumab inhibits angiogenesis and halts tumor growth [22] , including GBM proliferation [3,23] . Early clinical experience with bevacizumab in advanced colon, breast and lung cancers paved the way for it to become the most commonly used and thoroughly investigated antiangiogenic agent for the treatment of high-grade gliomas [24] . Several other proangiogenic molecules have been implicated in tumor angiogenesis and remain under active investigation. Among them are FGF, SDF-1α, angiopoietins, PDGF, IL-8, HIF-1α, neuropilins, endoglins and hepatocyte growth factor, among others [2,15,25–32] . Some, such as angiopoetins [33] and neuropilins [34] , interact directly with receptors on endothelial cells to promote new vessel growth and survival,
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Antiangiogenic therapies for glioblastoma while others, such as SDF-1α, work indirectly by attracting proangiogenic bone marrow-derived cells [35,36] . Integrins are cell adhesion receptors that help regulate the vascular extracellular matrix and can influence angiogenesis [37] , representing a separate target with therapeutic potential for GBM. Expressivity of the αvβ3 and αvβ5 integrin heterodimer subtypes found on the tumor’s growing edge directly correlates with glioma grade [38] , suggesting a central role in tumorigenesis. Integrins are found on glioma endothelial cells and during angiogenesis are required for endothelial cell migration and proliferation [17,39] . They may also play a role in preventing apoptosis [40] , thereby supporting endothelial cell survival [39] . Efficacy of antiangiogenic therapy ●●Bevacizumab
Early Phase II trials of bevacizumab in recurrent GBM provided evidence of clinical benefit and served as the impetus for the accelerated US FDA approval of bevacizumab in 2009. The BRAIN trial was a randomized Phase II noncomparative trial evaluating the efficacy of bevacizumab monotherapy and bevacizumab plus irinotecan in 167 patients with recurrent GBM [41] . The progression-free survival at 6 months (PFS6) was 42.6 and 50.3% for monotherapy and combination therapy, respectively, which represented a marked improvement over historical controls. For patients with a radiographic response or PFS >6 months, neurocognitive function at 24 weeks relative to baseline was improved or remained stable [42] . Importantly, bevacizumab proved to be well tolerated in these early clinical trials. In the BR AIN trial, 46% of patients treated with bevacizumab alone experienced grade 3 adverse events, the most common of which were hypertension and seizure. More serious adverse events included intracranial hemorrhage, seen in 2.4% of patients in the bevacizumab-only group and in 3.4% of patients in the combination therapy group [41] . Two additional trials provided further support for the utility of bevacizumab in the recurrent GBM setting. The first of these was performed at the National Cancer Institute and evaluated bevacizumab monotherapy in 47 patients with recurrent GBM. PFS6 and radiographic response rates were 29 and 35%, respectively [43] . The second trial – BELOB, a Phase II randomized
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study with assumed little crossover – evaluated the efficacy of bevacizumab, lomustine, and combination of the two agents. Combination treatment yielded an overall survival (OS) benefit at 9 months compared to treatment with either of the agents alone (59% for combination treatment, 42% for lomustine only, and 38% for bevacizumab only) [44] . Two larger, randomized, multicenter, Phase III trials, AVAglio and RTOG 0825, were conducted in newly diagnosed GBM and found a benefit in PFS but not OS. In both studies, patients were treated with standard therapy combined with bevacizumab or placebo. In the RTOG 0825 trial, PFS results favored bevacizumab (bevacizumab: 10.7 months vs placebo: 7.3 months; HR: 0.79; p = 0.007), but did not reach the prespecified thresholds of HR: 0.7 and p = 0.004 [45] . Importantly, criteria for enrollment into the RTOG 0825 trial specified a minimal amount of resected tissue rendering patients who received biopsies ineligible. Some would argue that this requirement excluded the subgroup of patients who might benefit the most from treatment with bevacizumab. In the AVAglio trial, the addition of bevacizumab to standard therapy during the initial 6-week period of chemoradiation produced a clinically meaningful and statistically significant improvement in PFS (6.2 months for the control arm vs 10.6 months for the bevacizumab arm; HR: 0.64; p 50% of those patients were able to decrease corticosteroids by an average of 59% [66] . More recent Phase III trials confirm antiedema effects of bevacizumab with 66% of patients initially on corticosteroids able to discontinue their use after treatment with bevacizumab, versus 44% in the control arm [63] . Several other trials reported corticosteroid reductions in 33–59% of patients with recurrent GBM following bevacizumab treatment [43,67–69] . Preclinical studies further highlight the potent effects of antiangiogenic therapy on peritumoral edema [9] . In three different orthotopic murine glioma models, cediranib significantly alleviated edema through normalization of tumor vasculature. Additionally, cediranib prolonged survival without concomitant effects on tumor [9] , suggesting that the survival benefits of cediranib may be attributable, at least in part, to its antiedema effect. Resistance mechanisms In the hopes of improving efficacy, significant efforts have been devoted to the study of mechanisms underlying resistance to treatment with bevacizumab and other antiangiogeneic agents. Resistance in this setting can be thought of as either intrinsic or acquired, although mechanisms underlying both may overlap [70] . Intrinsic resistance refers to the inherent ability of glioma tumor cells to elude antiangiogenic therapy. Clinical and preclinical evidence suggests that a significant minority of high-grade gliomas might be refractory to VEGF-targeted therapy from treatment onset. For example, treatment with cediranib in a xenograft model of GBM did not affect tumor growth [9] and some patients respond minimally or not at all to treatment with VEGF inhibitors [11,71] . Inherent resistance may stem from redundant proangiogenic signaling pathways or from the existence of a pool of glioma stem cells that reside in a quiescent state unresponsive to antiangiogenic therapy [72,73] . After initial failed treatment with bevacizumab, use of a second-line bevacizumab containing regimen is typically ineffective. In this setting, PFS and response rates are extremely poor, supporting the notion of acquired resistance to antiangiogenic therapy [74] . Modes of acquired resistance under investigation include [72] :
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Table 1. Recent selected trials of antiangiogenic therapy for glioblastoma. Study, year (trial)
n
Design
Regimens
Friedman et al., 2009 (BRAIN)
167
Phase II randomized in rGBM
Kreisl et al., 2009 (NCI) Field et al., (CABARET)
67
Phase II prospective in rGBM
122
Phase II randomized in rGBM
Taal et al., 2013 (BELOB)
148
Phase II randomized in rGBM
Wick et al., 2013 (AvaGlio)
921
Phase III randomized in nGBM
Gilbert et al., 2013 (RTOG 0825)
637
Phase III randomized in nGBM
Batchelor et al., 2013 (REGAL)
325
Phase III randomized in rGBM
Stupp et al., 2013 (CENTRIC)
545
Phase III randomized in rGBM with methylated MGMT
PFS
OS
Median 6 months (months) (%)
Median (months)
9 months (%)
Bev alone Bev + IRI Bev alone
NA NA 4
42.6 50.3 29
10 9.5 7.8
NA NA NA
Bev alone Bev + carboplatin Bev alone Lomustine alone Bev + lomustine RT/TMZ + TMZ/Plc XRT/TMZ + TMZ/Bev RT/TMZ + TMZ/Plc XRT/TMZ + TMZ/Bev Cediranib alone Lomustine alone Cediranib + lomustine RT/TMX + TMZ/CIL TMZ/RT + TMZ/Plc
NA NA 3 2 4 6.2 10 7.3 10.7 3.1 4 2.5 13.5 10
24 26 18 11 41 NA NA NA NA NA NA NA NA NA
NA NA 38 43 59 NA NA NA NA NA NA NA NA NA
6.4 6 NA NA NA 16.8 16.9 16.1 15.7 8 9.4 9.8 26.3 26.3
Ref.
[41] [43] [62] [44]
[63] [64] [65]
[60]
Bev: Bevacizumab; CIL: Cilengitide; IRI: Irinotecan; MGMT: O6-methylguanine-DNA methyltransferase; NA: Not applicable; nGBM: Newly diagnosed glioblastoma; OS: Overall survival; PFS: Progression-free survival; Plc: Placebo; rGBM: Recurrent glioblastoma; RT: Radiation therapy; TMZ: Temozolamide.
●● Adaptive upregulation of proangiogenic
signaling pathways; ●● Recruitment of bone marrow derived
proangiogenic cells to the tumor site; ●● Transformation to a more invasive glioma
phenotype; ●● Promotion of autophagy.
Growth factors with increased expression during periods of resistance to anti-VEGF therapy include FGF-1, FGF-2, Ephrin-A1 (Eph-A1), Eph-A2, angiopoietin-1, VEGF, PlGF, granulocyte colony-stimulating factor, SDF-1α, stem-cell factor, signal transducer and activator of transcription 3 (STAT3) and osteopontin [11,75–78] . Release of these angiogenic factors can be induced by hypoxia, which itself may be provoked by excessive vessel pruning in the setting of angiogenesis inhibition. The upregulation of proangiogenic factors in response to anti-VEGF therapy may have additional clinical implications in that discontinuation of the treatment could result in accelerated tumor growth [70] . Bone marrow-derived proangiogenic cells have also been implicated in acquired resistance to antiangiogenic therapy [28,72,79] . These include tumor-activated macrophages, granulocytes and
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precursor myeloid cells, all of which are recruited to the tumor site in large quantities during resistance and tumor progression [9,80,81] . These cells stimulate the expression of cytokines, growth factors and proteases which may help to promote tumor growth. Precursor myeloid cells, including endothelial and pericyte progenitors, support angiogenesis and neovascularization by differentiating into cells that are essential to the structure and integrity of new vasculature [82,83] . Recruitment of myeloid precursor cells may be associated with the activation of p-STAT3, an important signaling molecule. AZD1480 is an inhibitor of the JAK/STAT pathway that has been used in combination with anti-VEGF TKI treatment in xenograft models of GBM. The combination reduced the influx of proangiogenic macrophages to the tumor site and improved survival [78,84] . Antiangiogenic therapy may also promote resistance by encouraging transformation to a more invasive and mesenchymal glioma phenotype [85,86] . This transformation is likely stimulated by an increase in tumor hypoxia through the upregulation of c-Met expression [87] . In preclinical models, cabozantinib (XL184), a co-inhibitor of c-MET and VEGF-R, amplifies the antiangiogenic phenomena and halts tumor growth
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B
C
D
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Figure 1. Effects of bevacizumab on tumor-associated vasogenic edema and contrast-enhancing tumor progression in glioblastoma multiforme (facing page). T2/FLAIR imaging obtained (A) immediately prior to and (B) 4 months after initiation of bevacizumab. Post-contrast T1 imaging obtained (C) immediately prior to and (D) 4 months after initiation of bevacizumab.
over blockade of VEGF-R alone [88] . Preliminary Phase II trial results of this agent revealed some efficacy in recurrent GBM [89] , but final results are pending. Onartuzamab, an antibody that inhibits MET, is currently in a Phase II clinical trial as combination therapy with bevacizumab for GBM. Predictive biomarkers Investigations into antiangiogenic therapy resistance mechanisms have gone hand-in-hand with efforts to identify biomarkers of response. Notable candidates have included imaging and serum markers of vascular normalization, which together can be viewed as the ‘vascular normalization index’. In a prospective Phase II trial of recurrent GBM, one dose of cediranib decreased tumor permeability on MRI in the subset of patients who achieved response to therapy and increased overall survival. No survival benefit was observed in patients whose initial permeability imaging was unaffected by treatment [11] . Likewise, in a subset of newly diagnosed GBM patients, the addition of cediranib to standard of care treatment with radiation and temozolomide increased vascular perfusion on MRI. This change in perfusion was evident early in treatment and was associated with an improvement in overall survival, suggesting that early imaging-based response may serve as a predictive biomarker for antiangiogenic therapy [10] . Circulating biomarkers of response may also exist. For example, the level of serum collagen IV (thought to reflect vessel basement membrane thinning) following one dose of cediranib has been associated with a survival benefit [12] . Although important and suggestive, biomarker data remain to be validated in randomized clinical trials. Conclusion & future perspective GBM remains a lethal neoplasm with no effective long-term treatment. The discovery of References 1
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