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First Published Online September 8, 2008
The Oncologist, Vol. 13, No. 9, 978-992, September 2008; doi:10.1634/theoncologist.2008-0056
© 2008 AlphaMed Press

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Neuro-Oncology

Therapeutic Application of Noncytotoxic Molecular Targeted Therapy in Gliomas: Growth Factor Receptors and Angiogenesis Inhibitors

Ahmed Idbaiha,b,c, François Ducrayd, Monica Sierra Del Rioc, Khê Hoang-Xuana,b,c, Jean-Yves Delattrea,b,c

aINSERM, Unité 711, Paris, France; bUPMC Univ Paris 06, Laboratoire Biologie des Interactions Neurone-Glie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; cAP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie Mazarin, Paris, France; dINSERM, Unité 842, Université Claude Bernard Lyon 1, Hospices Civils de Lyon, Lyon, France

Key Words. Glioma • Targeted therapy • Angiogenesis • Growth factor receptor

Correspondence: Jean-Yves Delattre, M.D., Service de Neurologie Mazarin, Groupe hospitalier Pitié-Salpêtrière, 47-83, Boulevard de l'Hôpital, 75013 Paris, France. Telephone: 33-1-42-16-03-85; Fax: 33-1-42-16-04-18; e-mail: jean-yves.delattre{at}psl.aphp.fr

Received March 10, 2008; accepted for publication July 26, 2008; first published online in THE ONCOLOGIST Express on September 8, 2008.

Disclosure: The authors disclose that the article discusses therapeutics about tyrosine kinase inhibitors and antiangiogenic agents from various manufacturers and providers. The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the authors, planners, independent peer reviewers, or staff managers.


   Learning Objectives
Top
 Learning Objectives
Abstract
 Introduction
 Growth Factor Receptor...
 Antiangiogenic Therapies in...
 Clinical Evaluation of New...
 Author Contributions
 Acknowledgments
 References
 
After completing this course, the reader should be able to:

  1. Describe the key molecular pathways involved in the oncogenesis and angiogenesis of gliomas.
  2. Discuss the current use of targeted therapies in gliomas.
  3. Explain the clinical challenges in the future development of these agents.

This article is available for continuing medical education credit at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Growth Factor Receptor...
 Antiangiogenic Therapies in...
 Clinical Evaluation of New...
 Author Contributions
 Acknowledgments
 References
 
Growth factor receptors and angiogenesis play major roles in the oncogenesis of gliomas. Over the last several years, several noncytotoxic molecular targeted therapies have been developed against growth factor receptors and tumor angiogenesis. In gliomas, two main anti–growth factor receptor strategies have been evaluated in phase I/II clinical trials: (a) small molecule tyrosine kinase inhibitors (TKIs) and (b) monoclonal antibodies that target growth factors or growth factor receptors other than vascular endothelial growth factor (VEGF). Up to now, few glioma patients have responded to small TKIs (0%–14%) or monoclonal antibodies (three case reports) delivered as a single agent. Greater doses, combined therapies, as well as the identification of molecular biomarkers predictive of response and resistance are important in order to optimize drug delivery and improve efficacy.

Antiangiogenic therapies are promising for the treatment of gliomas. Thalidomide and metronomic chemotherapy were the first antiangiogenic strategies evaluated, but they have shown only modest activity. Recent studies of bevacizumab, an anti-VEGF antibody, and irinotecan, a topoisomerase I inhibitor, have demonstrated a high response rate, suggesting that targeted antiangiogenic therapies may play a significant role in the management of high-grade gliomas in the future. However, the toxicity profiles of these agents are not fully defined and the radiological evaluation of possible tumor response is challenging. Clinical evaluation of several VEGF receptor TKIs is currently ongoing; one of these inhibitors, cediranib, has already demonstrated interesting activity as a single agent. The integrin inhibitor cilengitide represents another promising strategy.


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Growth Factor Receptor...
 Antiangiogenic Therapies in...
 Clinical Evaluation of New...
 Author Contributions
 Acknowledgments
 References
 
Gliomas are the most frequent primary malignant brain tumors in adults. Over the last decades, their incidence has increased, particularly in the elderly [1, 2]. Gliomas are classified by the World Health Organization (WHO) into several subtypes according to their phenotype (oligodendroglioma, oligoastrocytoma, and astrocytoma) and their grade of malignancy (from WHO grade I to WHO grade IV).

Despite aggressive treatments, including maximal surgery, radiotherapy, and chemotherapy, the prognosis remains poor, particularly in patients with high-grade gliomas (WHO grade III and IV) [3–5].

Currently, the standard of care for WHO grade IV glioma patients, aged ≤70 years, consists of maximal surgery followed by radiotherapy with concomitant and adjuvant temozolomide, an alkylating chemotherapeutic [4]. This therapeutic schedule yields 1-year and 2-year survival rates of 61.1% and 26.5%, respectively. At relapse, there is no widely accepted standard of care and the prognosis is poor. When possible, a second tumor resection is usually recommended together with the implantation of interstitial BCNU (carmustine) wafers (Gliadel®; MGI Pharma, Inc., Bloomington, MN) [6]. Otherwise, patients receive second-line chemotherapy. Wong et al. [7] analyzed the outcomes of 225 patients with recurrent glioblastomas enrolled in eight consecutive phase II chemotherapy trials. That study is widely used as defining a "baseline" by which new studies are judged. The 6-month progression-free survival (PFS) rate was 15% and the median overall survival (OS) time was 25 weeks.

The oncogenesis of gliomas, particularly glioblastomas, is driven by several biological processes, including activated growth factor receptor signaling pathways and marked angiogenesis. Indeed, several growth factor receptors, such as the epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), C-Kit, and vascular endothelial growth factor receptor (VEGFR) are overexpressed, amplified, and/or mutated in gliomas. This gain of function activates downstream oncogenic signaling pathways. Moreover, prominent angiogenesis is a cardinal feature of malignant gliomas.

These findings, together with resistance to conventional cytotoxic therapeutics, emphasize the need for efforts to develop noncytotoxic targeted molecular therapies directed against the pathways involved in the oncogenesis of gliomas. To date, several molecules have been evaluated in clinical trials (Fig. 1).


Figure 1
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  		Figure 1. Simplified signaling pathways involved in gliomagenesis and site of action of molecular targeted therapies.

Abbreviations: Akt, v-akt murine thymoma viral oncogene homolog 1; CSK, c-Src kinase; EGFR, epidermal growth factor receptor; HGFR, hepatocyte growth factor receptor; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; PDGFR, platelet-derived growth factor receptor; PI3K, phosphatidylinositol 3'-kinase; PKC, protein kinase C; PLC, phospholipase C; PTEN, phosphatase and tensin homolog; SAHA, suberoylanilide hydroxamic acid; VEGFR, vascular endothelial growth factor receptor.

 
The purpose of this paper is to review the main studies evaluating targeted therapies in the clinical setting. Anti–growth factor receptor molecules and antiangiogenic drugs are considered separately, although this division is arbitrary because growth factor receptor signaling pathways and angiogenesis crosstalk in the oncogenic network (Fig. 1).


   GROWTH FACTOR RECEPTOR INHIBITORS
Top
 Learning Objectives
 Abstract
 Introduction
 Growth Factor Receptor...
Antiangiogenic Therapies in...
 Clinical Evaluation of New...
 Author Contributions
 Acknowledgments
 References
 
Specific EGFR Inhibitors

Reversible Small Molecule Tyrosine Kinase Inhibitors
EGFR (also named ErbB-1 or human epidermal growth factor receptor [HER]-1) is a 170-kDa receptor tyrosine kinase (RTK). It is a member of the ErbB family of receptors (ErbB-2 or HER-2/Neu, ErbB-3 or HER-3, ErbB-4 or HER-4). It is comprised of three major domains: (a) the extracellular domain, (b) the transmembrane domain, and (c) the cytoplasmic domain, which harbors the tyrosine kinase activity. Ligand binding (amphiregulin, EGF, transforming growth factor TGF-β, decorin, betacellulin, epiregulin, neuroregulin) to the extracellular domain of a monomer results in its homo- or heterodimerization, inducing phosphorylation of the tyrosine kinase domain, activating several signaling pathways, in particular: (a) phosphatidylinositol 3'-kinase/Akt/mammalian target of rapamycin (mTOR), (b) Ras/mitogen-activated protein kinase (MAPK), (3) phospholipase C (PLC)/protein kinase C (PKC), and (d) c-Src [9–11] (Fig. 1). These activated pathways are involved in several cell biological processes, including cell proliferation, angiogenesis, migration/adhesion, survival, and differentiation.

Activation of EGFR is observed in gliomas, notably in glioblastomas, but also at a lower rate in oligodendroglial tumors [12, 13]. This activation occurs through several molecular mechanisms: (a) protein overexpression, reported in ~60% of cases; (b) gene amplification, reported in ~40% of cases; (c) truncated transcripts encoding for a constitutionally active receptor, reported in ~20% (mainly EGFRvIII) of cases; and (d) mutation of the extracellular domain (15%) [14, 15]. These alterations, which are quite frequently combined in the same tumor [13], activate the EGFR downstream signaling pathways described above, promoting the oncogenic process (Fig. 1).

Considering the frequency and the variety of EGFR-activating molecular alterations in glioblastomas, EGFR appears a promising candidate for noncytotoxic molecular targeted therapies. Therefore, several strategies have been developed in order to block the EGFR signaling pathway, including small molecule tyrosine kinase inhibitors (TKIs), monoclonal antibodies, toxin-linked conjugates, and vaccine therapies. The first and second, to a lesser extent, strategies are the most advanced in their clinical development.

Two main EGFR small molecule TKIs have been evaluated in gliomas: (a) gefitinib (Iressa®; AstraZeneca Pharmaceuticals, Wilmington, DE) and (b) erlotinib (Tarceva®; OSI Pharmaceuticals, Melville, NY) (Table 1). These small molecules, which are orally delivered, block the ATP pocket of the EGFR intracellular tyrosine kinase domain and thus inhibit activation of downstream signaling pathways (and in theory the oncogenic process). Several phase I and II studies using erlotinib or gefitinib as single therapeutic agents have been conducted in recurrent and newly diagnosed gliomas, mainly recurrent glioblastomas. These agents have not been adequately studied in lower grade gliomas.


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  		Table 1. Erlotinib and gefitinib used as a single therapeutic agent or combined with other therapeutic modalities in glioma patients

 
Overall, the results have been disappointing if one considers the frequency of EGFR abnormalities observed in these tumors. Indeed, the response rates varied in the range of 0%–14% (Table 1). The median PFS time reported was approximately 8–12 weeks and the 6-month PFS rate varied in the range of 9%–14.3% in glioblastomas [16–24]. It is noteworthy that these molecules were well tolerated as single therapeutic agents, save for occasional rashes, diarrhea, and fatigue.

Several strategies have been proposed in order to improve the efficacy of EGFR small TKIs in gliomas. Some authors have suggested a better molecular selection of patients who may benefit from such targeted therapies. Indeed, several biomarkers predictive of response to small molecule TKIs have been proposed but still need to be validated. Haas-Kogan et al. [25] reported that glioblastoma patients whose tumor overexpressed and amplified EGFR gene had a better tumor response to small TKIs than patients whose glioblastoma did not have these molecular abnormalities. In addition, these investigators showed that low phospho-PKB/Akt level is associated with a good tumor response to erlotinib [25]. Mellinghoff et al. [26] demonstrated that glioblastoma coexpressing EGFRvIII and phosphatase and tensin homolog (PTEN) have a better response to EGFR small molecule TKIs. Lee et al. [13] reported that EGFR extracellular domain mutations may influence glioblastoma response to small TKIs. However, these results, obtained in retrospective studies, are debated and require validation in prospective studies [27, 28]. Two main mechanisms of resistance to small molecule TKIs have been proposed. First, Stommel et al. [29] showed that several RTKs could be activated simultaneously in gliomas maintaining activation of RTKs downstream signaling pathways. Thus, inhibition of one single activated RTK is insufficient and could be easily bypassed by other activated RTKs [29]. Second, in addition to RTK activation, growth factor receptor downstream signaling pathways can be activated through a mutation of ras or PTEN or an amplification of PI3K, inducing redundant activation of the signaling pathways [30–33]. Thus, combining EGFR inhibitors with inhibitors of mTOR, a distal target of the growth factor receptor signaling cascade (temsirolimus, sirolimus, everolimus), is a promising strategy (Table 1). Learn et al. [34] demonstrated that EGFRvIII is a major determinant of glioblastoma resistance to gefitinib. Indeed, dephosphorylation of EGFRvIII requires higher doses and longer exposure to gefitinib than dephosphorylation of nontruncated EGFR [34].

Currently, several ongoing clinical trials are combining small molecule TKIs with another therapeutic modality such as radiation and other targeted molecules (Table 1). The response rate in these studies varies in the range of 5.1%–26.3% [20, 35–44]. Toxicities include mucositis, rash, hematotoxicity, diarrhea, and fatigue, depending on the molecule used.

Anti-EGFR Antibodies
The first studies evaluating anti-EGFR antibodies were conducted 12 years ago [45, 46]. The authors showed that i.v. administrations of EMD55900 (a murine monoclonal antibody from Merck & Co., Inc., Whitehouse Station, NJ) were well tolerated and able to saturate intratumoral EGFR, but no therapeutic effect was observed in recurrent high-grade gliomas.

More recently, an EGFR murine humanized monoclonal antibody, cetuximab (Erbitux®; Merck & Co., Inc., Whitehouse Station, NJ), was developed. Little is known about the efficacy of cetuximab in glioma patients. Indeed, no clinical trial has been published. Anecdotally, Belda-Iniesta et al. [47] described three patients with recurrent EGFR-expressing glioblastomas who responded to cetuximab as a single therapeutic agent. The tolerance was acceptable with moderate asthenia and skin rash.

Recently, a phase I/II study combining cetuximab, radiation, and temozolomide was initiated in order to assess the safety and efficacy of this combination as first-line treatment for primary glioblastoma patients [48].

Targeted Toxin TGFa-PE38
TGFa-PE38 is a recombinant chimeric protein containing TGF-{alpha} fused to a synthetic form of Pseudomonas exotoxin A, PE38. TGF-{alpha} is a ligand of EGFR. Consequently, the toxin mainly affects glioma cells, which overexpress EGFR in comparison with normal brain cells. An initial report showed a response to intratumoral infusion of TP-38 in a recurrent glioblastoma [49]. More recently, a clinical study concluded that intracerebral convection-enhanced delivery of TP-38 was well tolerated and produced some interesting radiographic tumor responses [50]. Further investigations are warranted to evaluate the efficacy of this EGFR-targeting therapy.

Multiple Growth Factor Inhibitors
Imatinib mesylate (Gleevec®; Novartis, East Hanover, NJ) is a small molecule inhibiting the kinase activity of multiple growth factor receptors, including BCR-ABL, C-Kit, and PDGFR. C-Kit and PDGFR-{alpha} and PDGFR-β are involved in the oncogenesis of gliomas [51] (Table 2).


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  		Table 2. Imatinib used as a single therapeutic agent or combined with other therapeutic modalities in glioma patients

 
PDGFRA and PDGFRB are transmembrane RTKs. Binding of ligands (PDGFA to D) induces dimerization and cross-tyrosine phosphorylation of the intracellular domain. This activated form of the receptor induces several downstream signaling pathways such as the MAPK, PI3K, Src, and PLC pathways. It is noteworthy that PDGFRA and PDGFRB seem to have distinct activated signaling pathways [52, 53]. PDGFRs have been shown to be overexpressed in gliomas. This overexpression is correlated with the grade of malignancy [54–57]. Amplification of PDGFRA has been also reported in glioblastomas and a rare activating mutation in the PDGFRA sequence that deletes exons 8 and 9, encoding portions of the extracellular domain, has also been identified in a glioblastoma [58]. C-Kit is a RTK acting similarly to EGFR and PDGFR. Indeed, binding of ligand (stem cell factor) induces receptor dimerization and activation of several downstream signaling pathways, including Src family kinases, PLC-{gamma}, Ras/MAPK, and PI3K–Akt–mTOR [59, 60]. C-Kit expression is increased in glioblastomas [51, 61].

Consequently, inhibition of PDGFR and C-Kit also appears to be a potentially worthy strategy against glioblastomas.

Imatinib has been evaluated in several clinical trials in the recurrent glioma population. The most frequent side effects were hematologic toxicity, fatigue, vomiting, diarrhea, and liver disturbances. The objective response rate was approximately 6% (Table 2) [62–67]. Additional therapies, mainly with hydroxyurea, may yield slightly higher objective response rates of 9%–20% [68–76].

New Growth Factor Receptor Inhibitors and Other Related Molecular Targeted Strategies
Irreversible EGFR inhibitors, such as Tovok® (BIBW2992; Boehringer Ingelheim Pharmaceuticals, Ingelheim, Germany) and pelitinib (EKB-569; Wyeth Pharmaceuticals, Madison, NJ), bind covalently to EGFR and are an interesting alternative to reversible EGFR inhibitors. Indeed, these drugs may overcome the resistance to reversible EGFR inhibitors [77, 78].

Therapeutic targeting of the hepatocyte growth factor (scatter factor)/hepatocyte growth factor receptor (HGFR) (c-MET) pathway, including the downstream kinase c-Src, has been shown to be promising in preclinical models of malignant gliomas [79–85]. Therefore, phase I/II clinical trials have been initiated using dasatinib (BMS354825; Sprycel®, Bristol Myers Squibb, Princeton, NJ), an Src-family protein–TKI, alone or in combination with erlotinib, in recurrent malignant gliomas [86].

New growth factor inhibitors such as lapatinib (Tykerb®; GlaxoSmith-Kline, Philadelphia), a dual EGFR and ErbB-2 inhibitor, and canertinib (Pfizer, New York), a panErbB inhibitor, are emerging, but no published results are yet available in gliomas. Sunitinib (Sutent®; Pfizer, New York), inhibiting PDGFR, VEGFR, c-Kit and Flt-3, and sorafenib (Nexavar®; Bayer Pharmaceuticals Corporation, West Haven, CT, and Onyx Pharmaceuticals, Emeryville, CA), targeting Raf, PDGFR, and VEGFR, have demonstrated activity in preclinical models [87, 88]. Sorafenib, alone or in combination with temozolomide or erlotinib in recurrent glioma, is currently being evaluated in phase I/II studies. Similarly, sunitinib, either alone or in combination with irinotecan, is being studied in recurrent malignant gliomas through phase I/II studies [89].

In addition to growth factor receptor inhibitors, other strategies are being developed. The ubiquitin-26S proteasome pathway involved in nonlysosomal protein degradation is also a target for cancer therapy. Indeed, inhibition of the proteasome using bortezomib (Velcade®; Millennium Pharmaceuticals, Inc., Cambridge, MA) induces cell apoptosis mediated notably through stabilization of I{kappa}B{alpha} [90]. Several phase I/II studies are currently evaluating bortezomib, alone or in combination with other molecules, in glioma patients [91].

Histone deacetylases (HDACs) play a critical role in gene silencing. These molecules remove acetyl groups covalently linked to histones, inducing inhibition of gene transcription. Several preclinical studies have suggested that HDAC inhibitors might be useful in glioma treatment, inducing tumor cell death [92–98]. HDAC inhibitors such as romidepsin (Fujisawa Pharmaceuticals, Osaka, Japan) and suberoylanilide hydroxamic acid or vorinostat (Zolinza®; Merck & Co., Inc., Whitehouse Station, NJ) are under evaluation in recurrent malignant glioma patients [99].

The Ras–MAPK pathway is critical in glioma oncogenesis. Inhibition of Ras activation through post-translational farnesylation by farnesyl transferase has been shown as an interesting approach in glioma therapeutics. Currently, two farnesyl transferase inhibitors, lonafarnib (Sarasar®; Schering-Plough Corporation, Kenilworth, NJ) and tipifarnib (Zarnestra®; Johnson & Johnson Pharmaceutical) are being tested in phase I/II trials dedicated to primary or recurrent gliomas [100].

mTOR is a downstream component of the growth factor receptor–PI3K–Akt pathway, which is pivotal in gliomagenesis. Therefore, inhibition of this target contributes to turning off the aberrant activation of this pathway and reducing the aggressiveness of malignant gliomas. Temsirolimus (Torisel®; Wyeth Pharmaceuticals, Inc., Madison, NJ), everolimus (Certican®; Novartis Pharmaceuticals Corporation, East Hanover, NJ), and AP23573 (ARIAD Pharmaceuticals, Inc., Cambridge, MA) are three synthetic analogues of the antibiotic rapamycin (also termed sirolimus), which inhibits mTOR. After promising results in preclinical models, these agents are currently being evaluated either alone or in combination with other agents in glioma patients.


   ANTIANGIOGENIC THERAPIES IN GLIOMAS
Top
 Learning Objectives
 Abstract
 Introduction
 Growth Factor Receptor...
 Antiangiogenic Therapies in...
Clinical Evaluation of New...
 Author Contributions
 Acknowledgments
 References
 
Rationale
Angiogenesis is tightly correlated with the histological grading and prognosis of gliomas [101]. Glioma vasculature is structurally and functionally abnormal, leading to vasogenic edema, increased interstitial pressure, and heterogeneous delivery of oxygen and drugs [8]. VEGF is the key factor implicated in the angiogenesis of gliomas. It acts as a major vascular permeability factor and as a mitogen/survival promoter for endothelial cells [102, 103]. VEGF expression is stimulated by hypoxia, acidosis, and many growth factors (EGFR, PDGFR, HGFR, C-Kit, insulin-like growth factor receptor), and their downstream signaling pathways (PI3K–Akt, Ras–MAPK) are commonly activated in gliomas [8]. However, many other proangiogenic factors (such as basic fibroblast growth factor [bFGF], interleukin [IL]-1β, IL-6, IL-8, TNF-{alpha}, stromal cell–derived factor [SDF]-1{alpha}) are upregulated in gliomas, and this might explain how gliomas may escape a specific antiangiogenic therapy [8]. Consistent with this hypothesis is a recent study of a pan-VEGFR TKI, in which elevation of bFGF and SDF-1{alpha} plasma levels were correlated with tumor progression through anti-VEGF treatment [104].

The rationale for antiangiogenic therapy relies on several lines of evidence. First, since Folkman's seminal work, it has been well known that tumor development is angiogenesis dependent [105, 106]. Second, it has been demonstrated that antiangiogenic therapy is able to normalize the structure and function of abnormal neovasculature [8, 107, 108]. The normalization hypothesis states that antiangiogenic therapies may augment the effects of chemotherapy and radiotherapy by normalizing tumor vessels. If antiangiogenic therapy can restore normal blood flow and diminish vascular leakage, vasogenic edema, and interstitial pressure, it might facilitate the delivery of blood-administrated drugs [108]. Furthermore, normalizing tumor vessels might also reduce hypoxia, and thus make the tumor cells more sensitive to chemotherapy and radiation therapy [8, 108, 109]. Finally, recent data have demonstrated that glioblastoma cancer stem cells promote angiogenesis but also require angiogenesis for their development. Thus, antiangiogenic therapy might also target cancer stem cells [110–113].

Clinical Trials of Antiangiogenic Therapies

Thalidomide
Thalidomide (Thalidomid®; Celgene Corporation, Warren, NJ) has antiangiogenic activity by inhibiting bFGF and VEGF signaling [114] (Table 3). As a single agent, it has been demonstrated to have only modest activity [115–117]. The most frequent side effect was sedation. To date, phase II studies of thalidomide in association with BCNU or temozolomide have not shown a clear benefit when compared with historical studies of chemotherapy alone [118–121]. Several phase II trials of thalidomide in combination with chemotherapy (temozolomide or irinotecan), interferon, celecoxib, or isotretinoin are currently ongoing. Lenalidomide (Revlimid®; Celgene Corporation, Warren, NJ), a potent analogue of thalidomide, demonstrated minimal activity in a recent phase I study in recurrent high-grade glioma patients [122]. The only toxicity was a higher risk for thromboembolic disease.


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  		Table 3. Thalidomide and metronomic chemotherapy in glioma patients

 

Metronomic Antiangiogenic Chemotherapy
The antiangiogenic action of metronomic chemotherapy, that is, frequent regular administration of chemotherapy at low doses, was first demonstrated in a murine model of cyclophosphamide-resistant tumors [123]. When cyclophosphamide was administered on a conventional schedule all mice died from their tumors, but when cyclophosphamide was administered more frequently at a lower dose the tumors were potently inhibited because of endothelial apoptosis [123]. This approach was effective in preclinical glioma models [124]. This strategy, alone or in combination with other potential antiangiogenic agents (celecoxib, tamoxifen), has been evaluated in several phase I/II trials in recurrent gliomas (Table 3). Although reasonably well tolerated, these combinations have been demonstrated to have only limited activity [125–128]. Metronomic chemotherapy, however, might be more effective when combined with more potent angiogenesis inhibitors, and several studies are testing this hypothesis.

Anti-VEGF/VEGFR Therapies

Bevacizumab. Bevacizumab (Avastin®; Genentech, Inc., South San Francisco, CA) is a humanized IgG1 monoclonal antibody that selectively blocks VEGF. It was the first antiangiogenic therapy approved for use in oncology. In combination with conventional chemotherapy, bevacizumab resulted in longer OS times in metastatic colorectal cancer and metastatic, locally advanced or recurrent non-small cell lung carcinoma patients and led to longer PFS times in previously untreated metastatic breast cancer and locally advanced renal cancer patients [129]. In gliomas, despite evidence of activity in preclinical models, clinical development of bevacizumab was delayed initially because of the fear of central nervous system (CNS) hemorrhage [130, 131]. Stark-Vance first reported a high response rate (43%) in a series of recurrent high-grade glioma patients (n = 21) treated with bevacizumab and irinotecan [132]. Pope et al. [133] reported a similar high response rate (50%) in a retrospective study of recurrent high-grade glioma patients treated with bevacizumab in combination with irinotecan, carboplatin, or etoposide (Table 4). Vredenburgh et al. [134] reported the results of a phase II study conducted in 32 patients with recurrent grade 3 (n = 9) or grade 4 (n = 23) gliomas. Patients were treated with bevacizumab (10 mg/kg every 2 weeks) in combination with irinotecan (125 mg/m2, or 340 mg/m2 if patients were on enzyme-inducing antiepileptic drugs). Because of the potential risk for CNS hemorrhage, patients who were on anticoagulants were excluded. Radiographic responses (one complete and 19 partial responses) were observed in 20 of 32 patients (63%), which is much higher than the response rate observed with alkylating agents (<20%). The 6-month PFS rates were 30% and 56% in grade 4 and grade 3 gliomas, respectively, comparing favorably with historical controls [7]. No patient developed CNS hemorrhage. The most frequent serious side effects were thromboembolic complications. Other frequent side effects included grade 2 proteinuria and fatigue. The same authors subsequently reported their experience in a larger series of 35 patients with recurrent glioblastomas (23 of whom had had their results published previously) and found results confirming their earlier findings [135]. A CNS hemorrhage was observed in one patient. Seven patients completed 1 year of treatment, and in six of these patients, 18F-fluorodeoxyglucose positron emission tomography (PET) scans were hypometabolic, suggesting no residual tumor activity, demonstrating that this chemotherapy regimen had more than a dexamethasone-like effect. The 1-year OS rate was 37%, compared with the 21% usually observed in recurrent glioblastoma patients [135]. These promising results concerning the efficacy and safety profile of bevacizumab and irinotecan are consistent with other reports [136–146]. However, the links between VEGF expression, radiological response, and survival remain unclear.


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  		Table 4. Bevacizumab, cediranib, and cilengitide in glioma patients

 
In a retrospective study conducted on 45 patients, high VEGF expression correlated with radiographic response but not with 1-year survival. High carbonic anhydrase 9, a marker of hypoxia, was associated with poor survival [147]. Chen et al. [136] evaluated the predictive value of 18F-fluorothymidine PET scanning in patients with grade 4 (n = 15) and grade 3 (n = 4) gliomas treated with bevacizumab. A radiographic response was observed in 38% and a metabolic response was observed in 47% of patients. A metabolic response was observed as early as 1–2 weeks after treatment onset and was more predictive of OS (p = .003) than a radiographic response (p = .06). Norden et al. [142] analyzed the pattern of recurrence in patients (n = 23) treated with bevacizumab and irinotecan, and their observations suggest that bevacizumab might more efficiently suppress enhancing tumor recurrence than infiltrative tumor growth. Several studies of bevacizumab in combination with metronomic dosing of temozolomide or etoposide or with daily erlotinib in recurrent glioma patients are ongoing. In addition, a Radiation Therapy Oncology Group study is comparing bevacizumab in combination with temozolomide or irinotecan. A multicenter phase III study of bevacizumab in combination with chemoradiation in newly diagnosed glioblastoma patients is being planned.

Multiple Growth Factor Inhibitors Directed Against the VEGF Pathway. Vatalanib (PTK787/ZK222584, Novartis Pharmaceuticals Corporation, East Hanover, NJ) is an oral VEGFR TKI that also inhibits PDGFR, C-Kit, and colony stimulating factor 1 receptor (CSF1R). It has been studied in two phase I/II studies either alone or in combination with lomustine or temozolomide [148, 149]. It was well tolerated, but efficacy was limited. A phase II trial of vatalanib in combination with radiotherapy and temozolomide is ongoing. Cediranib (Recentin®, AZD2171; AstraZeneca Pharmaceuticals, Wilmington, DE) is a potent pan-VEGFR TKI with additional activity against PDGFRs and C-Kit. It is generally well tolerated; the most frequent side effects include diarrhea, dysphonia, and hypertension [150]. Batchelor et al. [104] reported the results of cediranib monotherapy in 16 patients with recurrent glioblastoma included in a phase II trial (Table 4). A decrease in tumor contrast enhancement was noticed in all patients 24 hours after treatment onset. A partial response was observed in nine of 16 patients (56%) and a minor response was observed in three patients (18%); the median OS time was 211 days (in comparison with 175 days in historical series). Dynamic contrast-enhanced magnetic resonance studies demonstrated that the vascular normalization (both structural and functional) induced by cediranib had a rapid onset and was prolonged but reversible. As a consequence, cediranib significantly reduced vasogenic edema and had a steroid-sparing effect. Tumor progression through treatment was associated with increased plasma levels of bFGF and SDF-1{alpha}, suggesting that glioblastomas might use these angiogenic pathways to escape VEGF pathway inhibition and that these pathways might therefore be potential targets for therapy [104].

A phase I study of cediranib in combination with lomustine is ongoing, and a randomized trial comparing cediranib alone with lomustine alone and with cediranib plus lomustine in combination is planned.

VEGF Intracellular Signaling Inhibitors. Enzastaurin (LY-317615, Eli Lilly and Company, Indianapolis, IN) is a synthetic macrocyclic bisindolemaleimide that selectively inhibits PKC-β by binding to its ATP-binding site. PKC-β mediates VEGF intracellular signaling. It is generally well tolerated [151]. A phase I study demonstrated single-agent activity, but a follow-up randomized, phase III study comparing lomustine with enzastaurin in recurrent malignant glioma patients was prematurely discontinued after an interim analysis demonstrated modest activity and a possibly inferior outcome [152]. However, preclinical data have demonstrated that enzastaurin might enhance radiation therapy efficacy, and this hypothesis is currently being tested in a phase I/II trial [153].

Integrin Inhibitors
Integrins are heterodimer transmembrane receptors for the extracellular matrix that play a role in cell adhesion and cell migration, namely, in endothelial cell migration, adhesion, and proliferation during angiogenesis. Cilengitide (EMD 121974; Merck & Co., Inc., Whitehouse Station, NJ) is a cyclic arginine–glycine–aspartic acid containing peptide that binds to and inhibits {alpha}vβ3 and {alpha}vβ5 integrins, which are specifically involved in angiogenesis. In a phase I study (n = 51) of recurrent high-grade glioma patients, cilengitide was well tolerated and was demonstrated to have some activity [154] (Table 4). An objective response was observed in five patients, with two patients demonstrating prolonged complete responses (>24 months). Preliminary results of a phase I/II study conducted in recurrent glioblastoma patients (n = 81) comparing two doses (500 mg versus 2,000 mg i.v. twice weekly) also suggested single-agent activity, with some patients experiencing prolonged responses of up to 2 years [155]. Preliminary results of another study in recurrent glioblastoma patients who required resection demonstrated delivery of the drug into the tumor [156]. Preliminary results of a phase II trial of cilengitide (500 mg i.v. twice weekly) added to radiotherapy and temozolomide conducted in 52 patients with newly diagnosed glioblastomas suggested efficacy in a subgroup of patients, with little or no additional toxicity [157].

Future Directions and Specific Issues of Antiangiogenic Therapies
The response rate and the patterns of responses observed in patients treated with bevacizumab and irinotecan in recurrent gliomas are encouraging. Further studies are needed to determine if the patients who benefit from this treatment belong to a particular molecular subgroup. The most powerful chemotherapy regimen in combination with bevacizumab and the best timing to initiate bevacizumab therapy (before, during, or after radiotherapy, or at recurrence) remain to be determined. Several other angiogenic inhibitors are currently undergoing clinical evaluation in gliomas. VEGF trap (Regeneron Pharmaceuticals, Tarrytown, NY) is a fusion protein that binds to VEGF and placental growth factor, thereby preventing VEGF from binding to its cell receptors. VEGF trap has demonstrated antitumor activity in preclinical glioma models, alone or in combination with radiotherapy [158]. A phase II study is currently ongoing, and a multicenter study is planned in newly diagnosed glioblastoma patients in combination with temozolomide and radiation. Sunitinib and sorafenib are two multitargeted TKIs with potent antitumor and antiangiogenic activity. Sunitinib has been approved for clinical use in advanced renal cell carcinoma and imatinib-resistant or intolerant gastrointestinal stromal tumors. It had single-agent activity in a preclinical glioma model and is being evaluated in phase II studies in gliomas [87]. Sorafenib has been approved for patients with advanced renal cell carcinoma. Two phase I/II studies of sorafenib in combination with other targeted therapies (temsirolimus, erlotinib, or tipifarnib) in recurrent glioblastoma patients and one phase II study of sorafenib in combination with adjuvant temozolomide in newly diagnosed glioblastoma patients are ongoing. Other antiangiogenic therapies undergoing clinical evaluation in gliomas include the multitargeted TKIs vandetanib (Zactima®; AstraZeneca Pharmaceuticals, Wilmington, DE), tandutinib (MLN 518, Millennium Pharmaceuticals, Inc., Cambridge, MA), and pazopanib (GW786034, GlaxoSmith-Kline, Philadelphia) and the VEGFR-2 peptide inhibitor CT-322 (AngioceptTM; Adnexus, Waltham, MA).

As illustrated by the bevacizumab–irinotecan or the cediranib experiences, antiangiogenic therapies decrease vascular permeability and thereby challenge the radiological criteria currently used to evaluate tumor response. There is concern that a response, according to standard MacDonald criteria, with these therapeutics might reflect only the antipermeability effects of these therapies and not their antitumor activity. Thus, new imaging techniques such as PET scans or magnetic resonance spectroscopy might be more powerful in evaluating true response rates [136, 159, 160].

There has been concern regarding the risk for CNS hemorrhage using bevacizumab, and antiangiogenic therapies in general, in glioma patients. The currently available studies show that this risk seems to be considerably lower than once feared. However, comparative studies are needed to correctly evaluate this risk. Because asymptomatic intratumoral hemorrhage is frequently detected by imaging in gliomas, studies are also necessary to determine if these patients are at a higher risk for CNS hemorrhage when treated with antiangiogenic therapies; however, a recent retrospective study suggests that this might not be the case [138]. Another important point concerns patients on anticoagulants, who have been excluded from studies with bevacizumab up to now. Preliminary data suggest that this risk may be acceptably low in this patient population, although definitive studies are lacking [142, 161].


   CLINICAL EVALUATION OF NEW DRUGS AND THEIR COMBINATION WITH CONVENTIONAL THERAPIES
Top
 Learning Objectives
 Abstract
 Introduction
 Growth Factor Receptor...
 Antiangiogenic Therapies in...
 Clinical Evaluation of New...
Author Contributions
 Acknowledgments
 References
 
Basic and preclinical studies are yielding many new targeted drugs of potential clinical interest. The major challenge is therefore to select and test these agents as quickly as possible, alone or in combination with "classic" treatments.

Randomized clinical trials remain the gold standard for the evaluation of new drugs. However, considering the number of new agents and the therapies that could be combined with them, glioma-drug development programs should be tailored to allow the testing of such a wide range of possible combinations. Although not without controversy, phase "0" trials might help by allowing pharmacodynamic evaluation of new drugs in a few patients over a short period of time. Indeed, these studies might avoid larger, time-consuming phase I and II trials for drugs or drug combinations that have unfavorable pharmacologic properties in phase 0 trials [162, 163]. Importantly, these studies, and also presurgical studies conducted in recurrent glioma patients before resection, might help select drugs with good penetration across the blood–brain tumor barrier, which is a critical parameter for brain tumor therapy [164]. Although the blood–brain barrier may be disrupted in some areas of the tumor, a substantial proportion of glioma cells are located within brain areas with an intact blood–brain barrier. Recent reports have suggested that some small molecules, such as imatinib, for example, are substrates for P-glycoprotein and other efflux pumps [165]. Surprisingly, despite the number of studies conducted using erlotinib and gefitinib, the penetration rate of the blood–brain barrier by these drugs remains uncertain, complicating the interpretation of their lack of efficacy [166].

Molecular characterization of gliomas may also contribute to the identification of patients who could theoretically benefit from new targeted drugs and may allow the construction of homogeneous cohorts of patients. Usually, a targeted drug is designed against a molecular abnormality that is involved in the oncogenic process but that is present in only a subgroup of tumors, which requires preliminary testing. Molecular-based clinical trials might putatively avoid negative results in a large clinical trial resulting from the inclusion of heterogeneous and unselected tumors [163].

Finally, the development of in vitro and in vivo models is critical for the preclinical evaluation of new therapeutic strategies. Indeed, strong results obtained in a relevant preclinical model will expedite clinical trials.


   AUTHOR CONTRIBUTIONS
Top
 Learning Objectives
 Abstract
 Introduction
 Growth Factor Receptor...
 Antiangiogenic Therapies in...
 Clinical Evaluation of New...
 Author Contributions
Acknowledgments
 References
 
Conception/design: Ahmed Idbaih, François Ducray, Jean-Yves Delattre

Collection/assembly of data: Ahmed Idbaih, François Ducray

Data analysis and interpretation: Ahmed Idbaih, François Ducray, Monica Sierra del Rio, Khê Hoang-Xuan

Manuscript writing: Ahmed Idbaih, François Ducray, Monica Sierra del Rio, Khê Hoang-Xuan, Jean-Yves Delattre

Final approval of manuscript: Ahmed Idbaih, François Ducray, Monica Sierra del Rio, Khê Hoang-Xuan, Jean-Yves Delattre


   ACKNOWLEDGMENTS
Top
 Learning Objectives
 Abstract
 Introduction
 Growth Factor Receptor...
 Antiangiogenic Therapies in...
 Clinical Evaluation of New...
 Author Contributions
 Acknowledgments
References
 
A.I. and F.D. contributed equally to this work.


   REFERENCES
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 Learning Objectives
 Abstract
 Introduction
 Growth Factor Receptor...
 Antiangiogenic Therapies in...
 Clinical Evaluation of New...
 Author Contributions
 Acknowledgments
 References
 

  1. Bauchet L, Rigau V, Mathieu-Daude H et al. French brain tumor data bank: Methodology and first results on 10,000 cases. J Neurooncol 2007;84:189–199.[CrossRef][Medline]
  2. Hess KR, Broglio KR, Bondy ML. Adult glioma incidence trends in the United States, 1977–2000. Cancer 2004;101:2293–2299.[CrossRef][Medline]
  3. Cairncross G, Berkey B, Shaw E et al. Phase III trial of chemotherapy plus radiotherapy compared with radiotherapy alone for pure and mixed anaplastic oligodendroglioma: Intergroup Radiation Therapy Oncology Group Trial 9402. J Clin Oncol 2006;24:2707–2714.[Abstract/Free Full Text]
  4. Stupp R, Mason WP, van den Bent MJ et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987–996.[Abstract/Free Full Text]
  5. van den 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 2006;24:2715–2722.[Abstract/Free Full Text]
  6. Bota DA, Desjardins A, Quinn JA et al. Interstitial chemotherapy with biodegradable BCNU (Gliadel) wafers in the treatment of malignant gliomas. Ther Clin Risk Manag 2007;3:707–715.[Medline]
  7. Wong ET, Hess KR, Gleason MJ et al. Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol 1999;17:2572–2578.[Abstract/Free Full Text]
  8. Jain RK, di Tomaso E, Duda DG et al. Angiogenesis in brain tumours. Nat Rev Neurosci 2007;8:610–622.[Medline]
  9. Hynes NE, Lane HA. ERBB receptors and cancer: The complexity of targeted inhibitors. Nat Rev Cancer 2005;5:341–354.[CrossRef][Medline]
  10. Yarden Y. The EGFR family and its ligands in human cancer. Signalling mechanisms and therapeutic opportunities. Eur J Cancer 2001;37(suppl 4):S3–S8.
  11. Zhang H, Berezov A, Wang Q et al. ErbB receptors: From oncogenes to targeted cancer therapies. J Clin Invest 2007;117:2051–2058.[CrossRef][Medline]
  12. Franco-Hernandez C, Martinez-Glez V, Alonso ME et al. Gene dosage and mutational analyses of EGFR in oligodendrogliomas. Int J Oncol 2007;30:209–215.[Medline]
  13. Lee JC, Vivanco I, Beroukhim R et al. Epidermal growth factor receptor activation in glioblastoma through novel missense mutations in the extracellular domain. PLoS Med 2006;3:e485.[CrossRef][Medline]
  14. Nicholas MK, Lukas RV, Jafri NF et al. Epidermal growth factor receptor–mediated signal transduction in the development and therapy of gliomas. Clin Cancer Res 2006;12:7261–7270.[Abstract/Free Full Text]
  15. Ohgaki H, Dessen P, Jourde B et al. Genetic pathways to glioblastoma: A population-based study. Cancer Res 2004;64:6892–6899.[Abstract/Free Full Text]
  16. Buie LW, Lindley C, Shih T et al. Plasma pharmacokinetics and cerebrospinal fluid concentrations of erlotinib in high-grade gliomas: A novel, phase I, dose escalation study. J Clin Oncol 2007;25:2054.
  17. Cloughesy T, Yung A, Vrendenberg J et al. Phase II study of erlotinib in recurrent GBM: Molecular predictors of outcome. J Clin Oncol 2005;23:1507.[Abstract/Free Full Text]
  18. Franceschi E, Cavallo G, Lonardi S et al. Gefitinib in patients with progressive high-grade gliomas: A multicentre phase II study by Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO). Br J Cancer 2007;96:1047–1051.[CrossRef][Medline]
  19. Lieberman FS, Cloughesy T, Fine H et al. NABTC phase I/II trial of ZD-1839 for recurrent malignant gliomas and unresectable meningiomas. J Clin Oncol 2004;22:1510.[Abstract/Free Full Text]
  20. Prados MD, Lamborn KR, Chang S et al. Phase 1 study of erlotinib HCl alone and combined with temozolomide in patients with stable or recurrent malignant glioma. Neuro Oncol 2006;8:67–78.[Abstract/Free Full Text]
  21. Raizer JJ, Abrey LE, Wen P et al. A phase II trial of erlotinib (OSI-774) in patients (pts) with recurrent malignant gliomas (MG) not on EIAEDs. J Clin Oncol 2004;22:1502.
  22. Rich JN, Reardon DA, Peery T et al. Phase II trial of gefitinib in recurrent glioblastoma. J Clin Oncol 2004;22:133–142.[Abstract/Free Full Text]
  23. Uhm JH, Ballman KV, Giannini C et al. Phase II study of ZD1839 in patients with newly diagnosed grade 4 astrocytoma. J Clin Oncol 2004;22:1505.
  24. Van Den Bent MJ, Brandes A, Rampling R et al. Randomized phase II trial of erlotinib (E) versus temozolomide (TMZ) or BCNU in recurrent glioblastoma multiforme (GBM): EORTC 26034. J Clin Oncol 2007;25:2005.
  25. Haas-Kogan DA, Prados MD, Lamborn KR et al. Biomarkers to predict response to epidermal growth factor receptor inhibitors. Cell Cycle 2005;4:1369–1372.[Medline]
  26. Mellinghoff IK, Wang MY, Vivanco I et al. Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med 2005;353:2012–2024.[Abstract/Free Full Text]
  27. Lassman AB, Abrey LE, Gilbert MR. Response of glioblastomas to EGFR kinase inhibitors. N Engl J Med 2006;354:525–526.[Free Full Text]
  28. Lassman AB, Rossi MR, Raizer JJ et al. Molecular study of malignant gliomas treated with epidermal growth factor receptor inhibitors: Tissue analysis from North American Brain Tumor Consortium Trials 01-03 and 00-01. Clin Cancer Res 2005;11:7841–7850.[Abstract/Free Full Text]
  29. Stommel JM, Kimmelman AC, Ying H et al. Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science 2007;318:287–290.[Abstract/Free Full Text]
  30. Broderick DK, Di C, Parrett TJ et al. Mutations of PIK3CA in anaplastic oligodendrogliomas, high-grade astrocytomas, and medulloblastomas. Cancer Res 2004;64:5048–5050.[Abstract/Free Full Text]
  31. Knobbe CB, Reifenberger J, Reifenberger G. Mutation analysis of the Ras pathway genes NRAS, HRAS, KRAS and BRAF in glioblastomas. Acta Neuropathol 2004;108:467–470.[CrossRef][Medline]
  32. Ohgaki H, Kleihues P. Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. J Neuropathol Exp Neurol 2005;64:479–489.[Medline]
  33. Rao RD, Mladek AC, Lamont JD et al. Disruption of parallel and converging signaling pathways contributes to the synergistic antitumor effects of simultaneous mTOR and EGFR inhibition in GBM cells. Neoplasia 2005;7:921–929.[CrossRef][Medline]
  34. Learn CA, Hartzell TL, Wikstrand CJ et al. Resistance to tyrosine kinase inhibition by mutant epidermal growth factor receptor variant III contributes to the neoplastic phenotype of glioblastoma multiforme. Clin Cancer Res 2004;10:3216–3224.[Abstract/Free Full Text]
  35. Brewer CJ, Suh JH, Stevens GHJ et al. Phase II trial of erlotinib with temozolomide and concurrent radiation therapy in patients with newly-diagnosed glioblastoma multiforme. J Clin Oncol 2005;23:1567.
  36. Chakravarti A, Berkey B, Robins HI et al. An update of phase II results from RTOG 0211: A phase I/II study of gefitinib with radiotherapy in newly diagnosed glioblastoma. J Clin Oncol 2006;24:1527.
  37. Das A, Badruddoja M, Tryciecky D et al. Phase I study of gefitinib and rapamycin in patients with recurrent or progressive glioblastoma (Gbm). J Clin Oncol 2005;23:1572.
  38. De Groot JF, Gilbert MR, Hess KR et al. Phase II study of combination carboplatin and erlotinib in patients with recurrent glioblastoma multiforme. J Clin Oncol 2007;25:2024.
  39. Doherty L, Gigas DC, Kesari S et al. Pilot study of the combination of EGFR and mTOR inhibitors in recurrent malignant gliomas. Neurology 2006;67:156–158.[Abstract/Free Full Text]
  40. Krishnan S, Brown PD, Ballman KV et al. Phase I trial of erlotinib with radiation therapy in patients with glioblastoma multiforme: Results of North Central Cancer Treatment Group protocol N0177. Int J Radiat Oncol Biol Phys 2006;65:1192–1199.[CrossRef][Medline]
  41. Nguyen TD, Lassman AB, Lis E et al. A pilot study to assess the tolerability and efficacy of RAD-001 (everolimus) with gefitinib in patients with recurrent glioblastoma multiforme (GBM). J Clin Oncol 2006;23:1507.
  42. Reardon DA, Quinn JA, Vredenburgh JJ et al. Phase 1 trial of gefitinib plus sirolimus in adults with recurrent malignant glioma. Clin Cancer Res 2006;12:860–868.[Abstract/Free Full Text]
  43. Rich JN, Reardon DA, Quinn JA et al. A phase I trial of gefitinib (ZD1839) plus rapamycin for patients with recurrent malignant glioma. J Clin Oncol 2005;23:1565.
  44. Robins HI, Wen PY, Chang SM et al. Phase I study of erlotinib and CCI-779 (temsirolimus) for patients with recurrent malignant gliomas (MG) (NABTC 04–02). J Clin Oncol 2007;25:2057.[Abstract/Free Full Text]
  45. Faillot T, Magdelenat H, Mady E et al. A phase I study of an anti-epidermal growth factor receptor monoclonal antibody for the treatment of malignant gliomas. Neurosurgery 1996;39:478–483.[CrossRef][Medline]
  46. Stragliotto G, Vega F, Stasiecki P et al. Multiple infusions of anti-epidermal growth factor receptor (EGFR) monoclonal antibody (EMD 55,900) in patients with recurrent malignant gliomas. Eur J Cancer 1996;32A:636–640.[CrossRef]
  47. Belda-Iniesta C, Carpeno Jde C, Saenz EC et al. Long term responses with cetuximab therapy in glioblastoma multiforme. Cancer Biol Ther 2006;5:912–914.[Medline]
  48. Combs SE, Heeger S, Haselmann R et al. Treatment of primary glioblastoma multiforme with cetuximab, radiotherapy and temozolomide (GERT)—phase I/II trial: Study protocol. BMC Cancer 2006;6:133.[CrossRef][Medline]
  49. Sampson JH, Reardon DA, Friedman AH et al. Sustained radiographic and clinical response in patient with bifrontal recurrent glioblastoma multiforme with intracerebral infusion of the recombinant targeted toxin TP-38: Case study. Neuro Oncol 2005;7:90–96.[Abstract]
  50. Sampson JH, Akabani G, Archer GE et al. Intracerebral infusion of an EGFR-targeted toxin in recurrent malignant brain tumors. Neuro Oncol 2008;10:320–329.[Abstract/Free Full Text]
  51. Joensuu H, Puputti M, Sihto H et al. Amplification of genes encoding KIT, PDGFRalpha and VEGFR2 receptor tyrosine kinases is frequent in glioblastoma multiforme. J Pathol 2005;207:224–231.[CrossRef][Medline]
  52. Heidaran MA, Beeler JF, Yu JC et al. Differences in substrate specificities of alpha and beta platelet-derived growth factor (PDGF) receptors. Correlation with their ability to mediate PDGF transforming functions. J Biol Chem 1993;268:9287–9295.[Abstract/Free Full Text]
  53. Shih AH, Holland EC. Platelet-derived growth factor (PDGF) and glial tumorigenesis. Cancer Lett 2006;232:139–147.[CrossRef][Medline]
  54. Di Rocco F, Carroll RS, Zhang J et al. Platelet-derived growth factor and its receptor expression in human oligodendrogliomas. Neurosurgery 1998;42:341–346.[CrossRef][Medline]
  55. Hermanson M, Funa K, Hartman M et al. Platelet-derived growth factor and its receptors in human glioma tissue: Expression of messenger RNA and protein suggests the presence of autocrine and paracrine loops. Cancer Res 1992;52:3213–3219.[Abstract/Free Full Text]
  56. Maxwell M, Naber SP, Wolfe HJ et al. Coexpression of platelet-derived growth factor (PDGF) and PDGF-receptor genes by primary human astrocytomas may contribute to their development and maintenance. J Clin Invest 1990;86:131–140.[Medline]
  57. Nistér M, Libermann TA, Betsholtz C et al. Expression of messenger RNAs for platelet-derived growth factor and transforming growth factor-alpha and their receptors in human malignant glioma cell lines. Cancer Res 1988;48:3910–3918.[Abstract/Free Full Text]
  58. Clarke ID, Dirks PB. A human brain tumor-derived PDGFR-alpha deletion mutant is transforming. Oncogene 2003;22:722–733.[CrossRef][Medline]
  59. Roskoski R Jr. Structure and regulation of Kit protein-tyrosine kinase—the stem cell factor receptor. Biochem Biophys Res Commun 2005;338:1307–1315.[CrossRef][Medline]
  60. Roskoski R Jr. Signaling by Kit protein-tyrosine kinase—the stem cell factor receptor. Biochem Biophys Res Commun 2005;337:1–13.[CrossRef][Medline]
  61. Puputti M, Tynninen O, Sihto H et al. Amplification of KIT, PDGFRA, VEGFR2, and EGFR in gliomas. Mol Cancer Res 2006;4:927–934.[Abstract/Free Full Text]
  62. Katz C, Barrios H, Abramoff R et al. Imatinib (STI 571) is active in patients (PTS) with high-grade gliomas progressing on standard therapy. J Clin Oncol 2004;22:1542.[Free Full Text]
  63. Marosi C, Vedadinejad M, Haberler C et al. Imatinib mesylate in the treatment of patients with recurrent high grade gliomas expressing PDGF-R. J Clin Oncol 2006;24:1526.
  64. Raymond E, Brandes A, Van Oosterom A et al. Multicentre phase II study of imatinib mesylate in patients with recurrent glioblastoma: An EORTC:NDDG/BTG Intergroup Study. J Clin Oncol 2004;22:1501.[Abstract/Free Full Text]
  65. van den Bent MJ, Brandes A, Frenay M et al. Multicentre phase II study of imatinib mesylate (Glivec®) in patients with recurrent anaplastic oligodendroglioma (AOD)/mixed oligoastrocytoma (MOA) and anaplastic astrocytoma (AA)/low grade astrocytoma (LGA): An EORTC New Drug Development Group (NDDG) and Brain Tumor Group (BTG) study. J Clin Oncol 2005;23:1517.
  66. Viola FS, Katz A, Arantes A et al. Phase II trial of high dose imatinib in recurrent glioblastoma multiforme (GBM) with platelet derived growth factor receptor (PDGFR) expression. J Clin Oncol 2007;25:2056.
  67. Wen PY, Yung WK, Lamborn KR et al. Phase I/II study of imatinib mesylate for recurrent malignant gliomas: North American Brain Tumor Consortium Study 99–08. Clin Cancer Res 2006;12:4899–4907.[Abstract/Free Full Text]
  68. Bota DA, Desjardins A, Quinn JA et al. Phase II trial of imatinib mesylate and hydroxyurea for adults with recurrent/progressive low-grade glioma. J Clin Oncol 2007;25:2053.
  69. Desjardins A, Quinn JA, Vredenburgh JJ et al. Phase II study of imatinib mesylate and hydroxyurea for recurrent grade III malignant gliomas. J Neurooncol 2007;83:53–60.[CrossRef][Medline]
  70. Dresemann G. Imatinib and hydroxyurea in pretreated progressive glioblastoma multiforme: A patient series. Ann Oncol 2005;16:1702–1708.[Abstract/Free Full Text]
  71. Dresemann G, Hosius C, Nikolova Z et al. Imatinib plus hydroxyurea in pretreated non-progressive glioblastoma (GBM)—A single center phase II study. J Clin Oncol 2006;24:1583.
  72. Friedman HS, Quinn J, Rich JN et al. Imatinib mesylate (Gleevec) plus hydroxyurea is an effective regimen in the treatment of recurrent malignant glioma. Phase 2 study results. J Clin Oncol 2005;23:1515.
  73. Reardon D, Quinn JA, Rich JN et al. Phase I trial of imatinib, hydroxyurea and RAD001 for patients with recurrent malignant glioma. J Clin Oncol 2006;24:Abstract 1580.
  74. Reardon DA, Egorin MJ, Quinn JA et al. Phase II study of imatinib mesylate plus hydroxyurea in adults with recurrent glioblastoma multiforme. J Clin Oncol 2005;23:9359–9368.[Abstract/Free Full Text]
  75. Sathornsumetee S, Reardon DA, Quinn JA et al. An update on phase I study of dose-escalating imatinib mesylate plus standard-dosed temozolomide for the treatment of patients with malignant glioma. J Clin Oncol 2006;24:1560.
  76. Sathornsumetee S, Rich JN, Vredenburgh J et al. Phase I trial of imatinib mesylate, hydroxyurea and vatalanib for patients with recurrent glioblastoma multiforme (GBM). J Clin Oncol 2007;25:2027.[Abstract/Free Full Text]
  77. Kwak EL, Sordella R, Bell DW et al. Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc Natl Acad Sci U S A 2005;102:7665–7670.[Abstract/Free Full Text]
  78. Li D, Ambrogio L, Shimamura T et al. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 2008;27:4702–4711.[CrossRef][Medline]
  79. Abounader R, Ranganathan S, Lal B et al. Reversion of human glioblastoma malignancy by U1 small nuclear RNA/ribozyme targeting of scatter factor/hepatocyte growth factor and c-met expression. J Natl Cancer Inst 1999;91:1548–1556.[Abstract/Free Full Text]
  80. Brockmann MA, Papadimitriou A, Brandt M et al. Inhibition of intracerebral glioblastoma growth by local treatment with the scatter factor/hepatocyte growth factor-antagonist NK4. Clin Cancer Res 2003;9:4578–4585.[Abstract/Free Full Text]
  81. Kim KJ, Wang L, Su YC et al. Systemic anti-hepatocyte growth factor monoclonal antibody therapy induces the regression of intracranial glioma xenografts. Clin Cancer Res 2006;12:1292–1298.[Abstract/Free Full Text]
  82. Lal B, Xia S, Abounader R et al. Targeting the c-Met pathway potentiates glioblastoma responses to gamma-radiation. Clin Cancer Res 2005;11:4479–4486.[Abstract/Free Full Text]
  83. Laterra J, Nam M, Rosen E et al. Scatter factor/hepatocyte growth factor gene transfer enhances glioma growth and angiogenesis in vivo. Lab Invest 1997;76:565–577.[Medline]
  84. Laterra J, Rosen E, Nam M et al. Scatter factor/hepatocyte growth factor expression enhances human glioblastoma tumorigenicity and growth. Biochem Biophys Res Commun 1997;235:743–747.[CrossRef][Medline]
  85. Martens T, Schmidt NO, Eckerich C et al. A novel one-armed anti-c-Met antibody inhibits glioblastoma growth in vivo. Clin Cancer Res 2006;12:6144–6152.[Abstract/Free Full Text]
  86. http://clinicaltrials.gov/ct2/results?term=dasatinib+and+glioma. Accessed August 15, 2008.
  87. de Boärd S, Herlin P, Christensen JG et al. Antiangiogenic and anti-invasive effects of sunitinib on experimental human glioblastoma. Neuro Oncol 2007;9:412–423.[Abstract/Free Full Text]
  88. Jane EP, Premkumar DR, Pollack IF. Coadministration of sorafenib with rottlerin potently inhibits cell proliferation and migration in human malignant glioma cells. J Pharmacol Exp Ther 2006;319:1070–1080.[Abstract/Free Full Text]
  89. http://clinicaltrials.gov/ct2/results?term=sunitinib+and+glioma. Accessed August 15, 2008.
  90. Yin D, Zhou H, Kumagai T et al. Proteasome inhibitor PS-341 causes cell growth arrest and apoptosis in human glioblastoma multiforme (GBM). Oncogene 2005;24:344–354.[CrossRef][Medline]
  91. http://clinicaltrials.gov/ct2/results?term=bortezomib+and+glioma. Accessed August 15, 2008.
  92. Chinnaiyan P, Vallabhaneni G, Armstrong E et al. Modulation of radiation response by histone deacetylase inhibition. Int J Radiat Oncol Biol Phys 2005;62:223–229.[CrossRef][Medline]
  93. Eypoglu IY, Hahnen E, Buslei R et al. Suberoylanilide hydroxamic acid (SAHA) has potent anti-glioma properties in vitro, ex vivo and in vivo. J Neurochem 2005;93:992–999.[CrossRef][Medline]
  94. Gensert JM, Baranova OV, Weinstein DE et al. CD81, a cell cycle regulator, is a novel target for histone deacetylase inhibition in glioma cells. Neurobiol Dis 2007;26:671–680.[CrossRef][Medline]
  95. Kim JH, Shin JH, Kim IH. Susceptibility and radiosensitization of human glioblastoma cells to trichostatin A, a histone deacetylase inhibitor. Int J Radiat Oncol Biol Phys 2004;59:1174–1180.[CrossRef][Medline]
  96. Komata T, Kanzawa T, Nashimoto T et al. Histone deacetylase inhibitors, N-butyric acid and trichostatin A, induce caspase-8- but not caspase-9-dependent apoptosis in human malignant glioma cells. Int J Oncol 2005;26:1345–1352.[Medline]