Targeting of Intracellular Growth Signaling
The abnormalities in cellular signal transduction pathways identified in malignant gliomas (Fig. 2) have already led to a first generation of targeted molecular drugs to inhibit these pathways in the clinical setting (Table 1). Initial forays into this realm have not been universally successful, but the data and experience gained demonstrate the pertinence of the approach.28 An example of initial success is the humanized monoclonal antibody against VEGF, bevacizumab.29 On the basis of high radiographic response rates and a modest toxicity profile, the US Food and Drug Administration (FDA) has granted accelerated approval for the use of bevacizumab in the treatment of recurrent GBM. This section briefly summarizes the current status of the evolving field of targeted molecular therapies in adult malignant gliomas.
Table 1. Selected Targeted Molecular Agents Currently in Clinical Development for High-Grade Glioma
|EGFR||Gefitinib (ZD1839)|| ||TKI|
| ||Erlotinib (OSI–774)|| ||TKI|
| ||Lapatinib (GW-572016)||HER-2||TKI|
| ||PF-00299804||HER-2, HER-4||TKI (irreversible)|
| ||BIBW2992||HER-2, HER-4||TKI (irreversible)|
| ||Cetuximab|| ||Monoclonal antibody|
| ||Nimotuzumab|| ||Monoclonal antibody|
|Farnesyl transferase||Lonafarnib (SCH 66336)|| ||FTI|
| ||Tipifarnib (R115777)|| ||FTI|
|HDAC||Vorinostat (SAHA)|| ||HDAC inhibitor|
| ||Valproic acid|| ||HDAC inhibitor|
| ||LBH589|| ||HDAC inhibitor|
|HGF/SF||AMG102|| ||Monoclonal antibody|
|HSP-90||17-AAG|| ||Blocks HSP-90 ATP binding|
|Integrins αvβ3, αvβ5||Cilengitide (EMD121974)|| ||Synthetic RGD peptide|
|mTOR||Sirolimus (rapamycin)|| ||mTOR inhibitor|
| ||Everolimus (RAD001)|| ||mTOR inhibitor|
| ||Temsirolimus (CCI-779)|| ||mTOR inhibitor|
| ||Ridaforolimus (AP23573)|| ||mTOR inhibitor|
|PDGFR-α||IMC3G3|| ||Monoclonal antibody|
| ||Dasatinib||Src, BCR/Abl, c-Kit, ephrin A2||TKI|
| ||Tandutinib (MLN518)||Flt3, c-Kit||TKI|
|PKC||Enzastaurin (LY31761)|| ||STKI|
|VEGF-A||Aflibercept (VEGF Trap)||VEGF-B, PlGF||Soluble decoy receptor|
| ||Bevacizumab|| ||Monoclonal antibody|
|VEGFR-2||Cediranib (AZD2171)||All VEGFR subtypes, PDGFR-β, c-Kit||TKI|
| ||CT-322||All VEGFR subtypes||Adnectin|
| ||Pazopanib||All VEGFR subtypes, PDGFR-α and β, c-Kit||TKI|
| ||Sorafenib||VEGFR-3, B-Raf, PDGFR-β, c-Kit, Ras, p38α||TKI|
| ||Sunitinib||PDGFR-β, Flt3, c-Kit||TKI|
| ||Vandetanib (ZD6474)||EGFR||TKI|
| ||XL-184||c-Met, RET, c-Kit, Flt3, Tie-2||TKI|
Malignant Gliomas Display Aberrant Proliferation and Apoptosis Signaling
Growth factor pathways that stimulate cell proliferation are constitutively activated in malignant gliomas (Fig. 2). This can be achieved through overexpression or genetic amplification of growth factor receptor genes (EGFR, ERBB2, PDGFRA, MET, etc), as well as through gene mutations that lead to ligand-independent signaling as occurs for the epidermal growth factor receptor vIII (EGFRvIII), a mutant that sends constitutive growth signals. Alternatively, intracellular signaling pathways can be constitutively activated when the positive signaling molecules are mutated and signal constitutively, as occurs for PI3K pathway subunits (PIK3A, PIK3R1) or when the negative regulators of the pathway are lost through gene loss or mutation (eg, the PTEN tumor suppressor). Usually, such progrowth signaling is not enough to induce tumor formation and needs to be accompanied by loss of critical cell “switches” that normally monitor cell growth. The 2 main tumor suppressor pathways that accomplish this task are those of the p53 and Rb pathways, which directly monitor cell cycle entry and progression. p53 activates the transcription of p21, a molecule that blocks cell cycle progression in the G1 phase of the cell cycle by binding and inhibiting the function of the cyclin D family of proteins.20 These are the regulatory subunits of the cyclin/cyclin–dependent kinase complexes that regulate cell cycle entry and progression by inducing the phosphorylation and inactivation of Rb. The Rb protein can prevent cell entry into S-phase by inactivating the E2F family of transcription factors that are critical for the initiation of DNA replication. Although p53 and Rb can be the direct targets of mutations, the inactivation of these cell cycle control pathways can also be achieved indirectly by mutation or overexpression of other signaling molecules in the pathway (Fig. 2). Another contributor that directs cell proliferation in gliomas is c-Myc,30 a transcription factor that drives the expression of cell cycle promoters such as cyclins and cyclin-dependent kinases while blocking the transcription of cell cycle inhibitors (CKI).
Excessive growth-stimulating signals emanating from growth factor receptors or overexpressed oncogenes such as Myc are sensed by the cell and will trigger a safeguard response that results in cell death through apoptosis. Apoptosis or programmed cell death is the outcome of a physiological response that leads to cell termination.31 It is the result of a precise signaling process that is initiated either at the cell surface (death receptor pathway) or intrinsically by intracellular signals such as extensive DNA damage. This process involves the activation of a series of proteins called caspases, which leads to the irreversible breakdown of cellular components and ultimately cell death. To overcome this limitation in their growth, tumors will typically also genetically inactivate proapoptotic pathways or activate the overexpression of genes that can promote cell survival. The inactivation of the p53 protein by mutation abrogates proapoptotic responses in the cell because this factor controls the transcription of both cell cycle arrest (p21CKI) and proapoptotic genes (Bax, Fas, etc).20 Genetic inactivation of caspases and other proteins directly involved in the apoptotic machinery have also been documented.32 Another mechanism through which the tumor can overcome apoptotic induction is the overexpression of factors that will prevent activation of the apoptotic cascade. One major antiapoptotic mediator that is overexpressed in gliomas is transcription factor NFκB.33 NFκB is well known as a mediator of immune and inflammatory responses, but it also activates the transcription of proteins that inhibit apoptosis such as members of the inhibitor of apoptosis (IAP) family (c-IAP, XIAP, and survivin). IAPs interact directly with activated caspases and can block their proapoptotic function. Furthermore, NFκB can induce the expression of Bcl-2 and Bcl-XL, which reside at the outer layer of the mitochondrial membrane and can prevent its permeabilization, a critical step in the activation of the apoptosome.
Although the tumor has developed strategies to overcome the physiological induction of apoptosis during its growth, in many cases the tumor cells remain sensitive to apoptosis induction by therapeutic agents. Classical chemotherapy and radiotherapy can induce apoptosis in the tumors, and new proapoptotic agents currently are being developed. As an example, there is great interest in tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a ligand for death receptors present at the surface of tumor cells.31
Clinical Targeting of Cell Surface Growth Factor Receptors
EGFR is one of the most attractive therapeutic targets in GBM.34 The EGFR gene is amplified and overexpressed in approximately 40% of primary GBMs, especially those of the “classical” subtype (Fig. 1). Nearly half of tumors with EGFR amplification also have a constitutively active EGFR mutant known as EGFRvIII, which has a large deletion in the extracellular domain and renders the receptor ligand independent for signaling. This deletion also engenders a unique codon, which is not found in the wild-type receptor, thereby creating a tumor-specific epitope that can be exploited for therapeutic targeting. Increased EGFR signaling drives tumor cell proliferation, invasiveness, motility, angiogenesis, and inhibition of apoptosis. Small-molecule EGFR inhibitors such as gefitinib and erlotinib (Table 1) are well tolerated in patients with malignant gliomas, but responses are infrequent and progression-free survival (PFS) is not prolonged.34 Neither the EGFR/HER-2 inhibitor lapatanib,35 nor the monoclonal antibody against EGFR, cetuximab,36 have proven to be effective.
Attempts to identify biomarkers to help predict response to EGFR inhibitors have yielded conflicting results. To the best of our knowledge, there is no convincing evidence of a correlation between EGFR expression in tumor tissue and response. Some studies found that tumors with EGFRvIII and intact PTEN37 and tumors with low phosphorylated Akt levels38 are more likely to respond to EGFR inhibitors. However, not all studies confirmed this initial observation.39
Recent phase 2 studies have combined EGFR inhibitors with temozolomide and radiotherapy for patients with newly diagnosed GBM. Conflicting results have been observed. Other current trials in patients with malignant glioma are evaluating irreversible EGFR inhibitors such as BIBW 2992 and PF-00299804, the dual EGFR and VEGF receptor (VEGFR) inhibitor vandetanib (ZD6474), and the humanized monoclonal antibody against EGFR, nimotuzumab. CDX-110, a peptide vaccine against the unique epitope of EGFRvIII, has a favorable toxicity profile and currently is being studied in combination with temozolomide in patients with newly diagnosed GBM.82 Finally, combinations of EGFR inhibitors with other targeted therapies, including inhibitors of mammalian target of rapamycin (mTOR) and VEGFR, are being evaluated (Table 1).
The PDGFR subtypes α and β and PDGF ligands A and B are also overexpressed in malignant gliomas, especially in the “proneural” subtype (Fig. 1).27, 40 This creates autocrine or paracrine loops that promote tumor cell proliferation. The PDGFR inhibitor imatinib mesylate was reported to have significant antitumor activity both in vitro and in orthotopic glioma models.41 Unfortunately, the drug proved inactive in clinical trials, with rare responses and no prolongation of PFS.42 Studies with more potent PDGFR inhibitors and agents with improved BBB penetration such as tandutinib (MLN518) currently are underway.
Clinical Targeting of Intracellular Signaling Molecules
The PI3K/Akt pathway is a critical regulator of tumor cell metabolism, growth, proliferation, and survival. Ligand binding to receptor tyrosine kinases increases activity in the pathway, which ultimately activates mTOR. Downstream effectors of mTOR have an array of biological functions that promote hypoxic adaptation and protein translation. In malignant gliomas, PI3K/Akt/mTOR signaling is frequently increased because of receptor tyrosine kinase overactivity (EGFR, PDGFR, and mesenchymal-epithelial transition factor [MET]), mutated oncogenic PI3K subunits, and/or loss of PTEN tumor suppressor activity (Fig. 2).21 Several mTOR inhibitors are undergoing evaluation in malignant gliomas, including sirolimus (rapamycin), temsirolimus (CCI-779), everolimus (RAD001), and ridaforolimus (AP23573). To date, mTOR inhibitors have demonstrated only minimal single agent activity against malignant gliomas.43, 44 A clinical trial of the dual PI3K/mTOR inhibitor, XL765, in combination with temozolomide for GBM is currently underway, but no preliminary data have been reported to date. Akt inhibitors are expected to enter clinical trials for malignant gliomas in the near future. Enzastaurin (LY317615) is a potent inhibitor of protein kinase C-β2 that also suppresses PI3K/Akt pathway signaling. After promising results in a phase 1 trial in patients with recurrent malignant gliomas,45 a phase 2 study was initiated. Unfortunately, the study was closed at interim analysis because of a lack of efficacy.
In addition to the PI3K/Akt/mTOR pathway, signal transduction from activated tyrosine kinases such as EGFR and PDGFR is mediated by the Ras/Raf/mitogen-activated protein kinase pathway. Activation of Ras requires localization to the intracellular surface of the cell membrane, a critical step that depends on farnesylation. Farnesyl transferase inhibitors (FTI) interfere with this process and have demonstrated promising activity in glioma models. Unfortunately, the FTI tipifarnib (R115777) did not demonstrate clear evidence of efficacy in a phase 2 trial in patients with recurrent malignant gliomas.46
Histone deacetylase (HDAC) inhibitors interfere with transcriptional regulation and can induce growth arrest, terminal differentiation, and apoptosis of tumor cells. The HDAC inhibitor vorinostat (suberoylanilide hydroxamic acid) proved effective in preclinical models but only modestly prolonged the 6-month PFS (PFS6) in a phase 2 trial in patients with recurrent GBM.47 Ongoing studies are investigating the combination of vorinostat with temozolomide and radiation. Other HDAC inhibitors currently in clinical trials for malignant gliomas include valproic acid and LBH589.
Resistance to Molecular Agents Targeting Tumor Growth Signaling Pathways
Results from the first generation of molecular agent trials targeted to proliferative pathways in malignant gliomas have been disappointing, with relatively rare radiographic responses and no significant prolongation of PFS reported. In an effort to improve on these initial results, an array of ongoing clinical trials combines novel molecular therapies with standard treatments such as radiation and chemotherapy.
One explanation for the initial failure of growth factor–targeted molecular drugs is that the targets critical for effective therapy have yet to be addressed. As a result of molecular profiling, network analysis, and correlative studies in clinical trials, novel targets that drive glioma growth and prevent tumor cell death are emerging rapidly. Among the promising therapeutic targets in early clinical development are MET, fibroblast growth factor receptor (FGFR), heat shock protein–90 (HSP–90), hypoxia-inducible factor 1α (HIF1α), cyclin-dependent kinases, and many others. In addition to the uncertainty about which targets require inhibition, there is an ongoing controversy regarding which cell types are most important. Glioma stem-like cells appear to initiate glioma formation and maintain the tumor mass. Inhibition of unique stem cell targets such as Notch and Sonic hedgehog may be required to overcome resistance to therapy.14, 48
Another explanation for the failure of targeted molecular agent monotherapy comes from data demonstrating that multiple receptor tyrosine kinases are coactivated in GBM cell lines and primary cultures. In preclinical models, multiple kinase inhibition is required to reduce signaling through the PI3K/Akt/mTOR pathway and decrease glioma cell survival.49 These data provide a compelling rationale for the myriad of ongoing trials of single agents that inhibit multiple targets or multiple agents that inhibit complementary pathways. Examples of multitargeted drugs that are being evaluated in malignant gliomas are presented in Table 1.
Drugs that inhibit single targets can also be combined to achieve multiple target inhibition. Particular interest has focused on the combination of EGFR inhibitors and mTOR inhibitors. Results from a phase 2 study of erlotinib and sirolimus in patients with recurrent GBM were disappointing,50 but several other studies are currently ongoing. One important obstacle to combination therapy with targeted molecular drugs is additive toxicity, which may limit the doses that patients can tolerate. For example, combinations of EGFR inhibitors with mTOR inhibitors have been associated with a high incidence of dermatologic toxicity and mucositis.51
Another factor that may interfere with the efficacy of targeted molecular drugs in malignant gliomas is insufficient penetration into the tumor tissue due to a partially intact BBB or an active drug efflux transporter. Due to the difficulty in obtaining tumor tissue in the brain tumor patient population, few clinical trials have successfully measured drug levels in tumor tissue. However, neuro-oncologists are increasingly recognizing that it is critical to obtain and study tumor tissue whenever possible.37, 52 Tissue studies permit assessments of drug penetration, degree of target inhibition in vivo, and resistance mechanisms. This information will facilitate the rational design of future trials and should increase the efficiency of clinical testing.
Targeting of Intercellular Signaling: Inhibition of Angiogenesis
As alluded to earlier, treatment directed toward new vessel growth in malignant gliomas has proven to be one of the most promising areas of targeted molecular therapy. To appreciate this, it is important to review the current understanding of angiogenesis in malignant gliomas and then examine the various approaches used to target these events with therapeutics.
Overview of Angiogenesis in Malignant Gliomas
Extensive experimental data support the concept that angiogenesis is required for malignant glioma growth.53, 54 The process is driven primarily by tumor-secreted VEGF-A, but there are a large number of alternative secreted proangiogenic factors, including basic FGF (bFGF), angiopoietins, PDGF, interleukin-8 (IL-8), and hepatocyte growth factor/scatter factor (HGF/SF). Endothelial cells in the vicinity of the tumor express VEGFR2, which establishes a paracrine signaling loop that stimulates endothelial cell growth and proliferation. The level of VEGF production in a tumor increases with the degree of malignancy. In a study of surgical glioma specimens, high-grade tumors produced greater than 10-fold more VEGF compared with low-grade tumors.55 A subset of targeted molecular therapy for malignant gliomas includes agents that interfere with angiogenesis. The majority of the antiangiogenic drugs that have been evaluated in clinical trials to date interfere with the VEGF pathway by directly blocking ligand or receptor. However, there is increasing interest in targeting proangiogenic molecules that function by alternative mechanisms.29
For example, the neuropilins are nontyrosine kinase receptors that are activated by VEGF binding and potentiate VEGFR signaling. Neuropilin-1 also facilitates HGF/SF signaling.56 The angiopoietins (Ang-1 and Ang-2) are involved in the stability and maintenance of the tumor vasculature. Binding of Ang-2 to its cognate receptor, Tie-2, serves to destabilize vessels, which is a requirement for angiogenesis to proceed.57 Ang-2 inhibitors are therefore of interest as therapeutic agents.58 Notch inhibitors may also prove effective. Notch receptors on tumor endothelial cells are activated by transmembrane jagged and delta-like ligands on the surfaces of neighboring cells. Inhibition of delta-like ligand 4 (Dll4) on endothelial cells in preclinical models promotes the growth of an abnormal neovasculature with reduced perfusion and tumor growth.59 Finally, tumor cells secrete chemokines that serve to recruit proangiogenic myeloid cells to the tumor. For this reason, inhibitors of specific chemotactic signaling may have therapeutic value.54
There is also evidence that antiangiogenic treatments may selectively target glioma stem-like cells.14, 48 Recent data suggest that stem-like cells are highly resistant to treatment and proangiogenic. Glioma stem-like cells exist in a “vascular niche,” in the microenvironment created by tumor endothelium. As such, antiangiogenic treatments that disrupt tumor vasculature may preferentially target this subpopulation and help to overcome the marked treatment resistance of malignant gliomas.
Therapeutic Targeting of Angiogenesis: VEGF Inhibitors
After bevacizumab was approved by the FDA for colon cancer, several neuro-oncology centers began to use it to treat patients with recurrent malignant glioma, often in combination with irinotecan. In the first published report, 19 of 29 patients (66%) treated with the combination achieved radiographic responses.60 Historical data from recurrent GBM trials demonstrated a response rate of only 5% to 8% with temozolomide therapy. Despite concerns about the risk of hemorrhage in brain tumor patients, only 1 patient was reported to have an intracerebral hemorrhage. A large number of retrospective series have now been published, with response rates of 25% to 74% reported, and PFS6 rates of 32% to 64%,5, 61–66 which is superior to the 21% PFS6 rate reported for temozolomide.67 These reports demonstrated that bevacizumab therapy leads to rapid reductions in peritumoral edema, often permitting a decrease in dose or even cessation of corticosteroid use. These studies also indicated that bevacizumab treatment is well tolerated in most cases. The risk of intracranial hemorrhage is low. Common toxicities related to bevacizumab therapy in the malignant glioma population include hypertension, proteinuria, fatigue, thromboembolic events, and wound-healing complications.
The first phase 2 trial of bevacizumab and irinotecan was conducted in 35 patients with recurrent GBM and 33 patients with recurrent anaplastic glioma.68 The radiographic response rate of approximately 60% was consistent with retrospective data, as was the PFS6 rate (43% for GBM patients and 59% for anaplastic glioma patients, compared with 21%67 and 46%,69 respectively).
The accelerated FDA approval of bevacizumab for recurrent GBM was based on 2 subsequent phase 2 trials. The first trial randomly assigned 167 patients with recurrent GBM to bevacizumab therapy with or without irinotecan.70 Response rates were reported to be between 28% and 38%, and PFS6 rates ranged from 43% to 50%. As had been reported in previous studies, most patients reduced their corticosteroid doses by 50% or more due to the marked antipermeability effect of bevacizumab. Adverse events were infrequent, with 8 (4.9%) intracerebral hemorrhages reported, the majority of which were not life-threatening, and 23 (14.1%) thromboembolic complications noted.71 The other phase 2 trial evaluated by the FDA involved bevacizumab monotherapy in 48 heavily pretreated patients with recurrent GBM.72 The radiographic response rate was 35%, and the PFS6 rate was 29%. In addition to hemorrhagic and thromboembolic complications, common toxicities observed in these studies included hypertension, proteinuria, fatigue, and wound-healing complications.
Ongoing phase 3 studies are evaluating the combination of bevacizumab with temozolomide and radiotherapy. The results will be of great interest because of the uncertainty regarding the impact of bevacizumab on overall survival. Combinations of bevacizumab and other chemotherapeutics and targeted molecular drugs are also currently in clinical trials. Aflibercept (VEGF-Trap) is a soluble decoy VEGF receptor fused to an immunoglobulin constant region that binds VEGF-A, VEGF-B, and placental growth factor (PIGF). A phase 2 study in recurrent malignant gliomas is ongoing, as is a phase 1/2 study in combination with temozolomide and radiotherapy for patients with newly diagnosed GBM.
In addition to VEGF inhibitors, small molecule inhibitors of VEGFR have been tested in recurrent malignant gliomas. Cediranib (AZD2171) inhibits all known subtypes of VEGFR and was evaluated in a phase 2 trial of patients with recurrent GBM. Results were comparable to those reported for bevacizumab, with a response rate of 56% and a PFS6 rate of 26%.73 A striking steroid-sparing effect was observed. The drug was largely well tolerated, with hypertension, diarrhea, and fatigue as the most common adverse effects. Using dynamic contrast-enhanced magnetic resonance imaging (MRI) scans, the authors demonstrated that cediranib therapy reduced blood vessel size and permeability. These are the first clinical data to support the hypothesis that antiangiogenic therapy may transiently “normalize” the dilated, abnormally permeable tumor vasculature.53 The presumption that vascular normalization may improve chemotherapy delivery and reduce hypoxia provides a solid rationale for combining antiangiogenic therapies with chemotherapy and radiotherapy. A vascular normalization index has been proposed to predict survival after antiangiogenic therapy.74 Other VEGFR inhibitors of interest for malignant gliomas are listed in Table 1.
Other Antiangiogenic Approaches
In addition to VEGF or VEGFR inhibition, a variety of other approaches may have antiangiogenic activity. Because of its role in pericyte recruitment,75 inhibition of PDGFR may prove useful. Several trials of PDGFR and dually targeted VEGFR/PDGFR inhibitors are ongoing, as noted earlier. The integrins αvβ3 and αvβ5 are highly expressed by tumor endothelial cells, in which they interact with extracellular matrix (ECM) proteins to facilitate angiogenesis and invasion.76 Cilengitide (EMD121974) inhibits these integrins and appears promising in GBM patients with methylation of the MGMT gene promoter.77
Mechanisms of Resistance to Antiangiogenic Therapy
Although antiangiogenic therapies prolong PFS, further progression of disease is inevitable. Tumors that progress during antiangiogenic therapy cannot often be treated successfully thereafter, and most patients die of the disease within a few months. In the cediranib study, serum levels of the proangiogenic factors bFGF, stromal-derived factor 1α (SDF1α), and soluble VEGFR2 increased at the time of failure.73 These alternative proangiogenic pathways may drive angiogenesis in the setting of VEGFR inhibition. Other preclinical78 and MRI data5 suggest that anti-VEGF therapy may promote an infiltrative tumor growth pattern with co-option of existing cerebral blood vessels. Combining antiangiogenic therapy with anti-invasion therapy may therefore delay disease progression. Studies combining cediranib (pan-VEGFR inhibitor) with cilengitide (integrin inhibitor) and bevacizumab (neutralizing VEGF antibody) with dasatinib (PDGFRbeta inhibitor) currently are ongoing. Another potential mechanism of resistance to antiangiogenic therapies involves increased PDGF signaling. PDGF promotes stabilization of the neovasculature by recruiting pericytes and facilitating pericyte-endothelial cell interactions.75 Preclinical data suggest that dual VEGFR/PDGFR inhibition potentiates antiangiogenic efficacy and reduces resistance to therapy,79 and this approach is currently being evaluated in clinical trials.
Targeted Molecular Therapy: Summary and Future Outlook
Most human cancers, including high-grade gliomas, have abnormalities in cellular signal transduction pathways. Targeted molecular drugs that inhibit these pathways have potential therapeutic value (Table 1). It is important not to overstate this prospect because the majority of targeted molecular drugs that have been evaluated in malignant gliomas to date have been disappointing, with response rates of 10% to 15% or less and no prolongation of survival.28 In the case of EGFR inhibitors, for example, selected patients do respond, but reliable predictors of response have not been identified. An exception is the humanized monoclonal antibody against VEGF, bevacizumab.29 Antiangiogenic therapies that target VEGF or VEGFR produce striking radiographic responses in many patients, relieve symptoms, and prolong PFS. On the basis of high radiographic response rates and a modest toxicity profile, the FDA recently granted accelerated approval for bevacizumab in the treatment of recurrent GBM. Although its impact on overall survival has not been assessed, there is a concern that aggressive tumor growth after the failure of antiangiogenic treatment may diminish any survival benefit.
Our emerging knowledge of the molecular pathophysiology of malignant gliomas will improve therapeutic target selection in the future. Rigorous preclinical testing is needed to identify combinations of drugs and targets that are most likely to be effective and tolerable. Targets such as HSP-90 and HDAC are of particular interest as therapeutic targets because their function influences many other signaling molecules that may promote tumor cell growth and proliferation. Studies of resistance to antiangiogenic therapy are needed to optimize the use of bevacizumab and other VEGF or VEGFR inhibitors. Clinical trials that incorporate tumor tissue and molecular endpoints will help us to understand why certain drugs succeed or fail in individual tumors. Although the initial results have been disappointing, targeted molecular agents hold tremendous promise. We remain optimistic that the ultimate goal of identifying targeted molecular therapies with durable antitumor efficacy will be realized by 2020.