Curr Oncol Rep (2014) 16:379 DOI 10.1007/s11912-014-0379-z
NEURO-ONCOLOGY (M GILBERT, SECTION EDITOR)
Targeted Therapy in Gliomas Mohamed Ali Hamza & Mark Gilbert
# Springer Science+Business Media New York 2014
Abstract The survival outcome of patients with malignant gliomas is still poor, despite advances in surgical techniques, radiation therapy and the development of novel chemotherapeutic agents. The heterogeneity of molecular alterations in signaling pathways involved in the pathogenesis of these tumors contributes significantly to their resistance to treatment. Several molecular targets for therapy have been discovered over the last several years. Therapeutic agents targeting these signaling pathways may provide more effective treatments and may improve survival. This review summarizes the important molecular therapeutic targets and the outcome of published clinical trials involving targeted therapeutic agents in glioma patients. Keywords Malignant gliomas . Gliomas . Radiation therapy . Chemotherapeutic agents . Oncology . Neuro-oncology . Molecular targets . Glioma patients . Central nervous system (CNS) . Flioblastoma (GBM) . Anaplastic gliomas . Therapeutic agents
Malignant gliomas refer to WHO grade III (anaplastic gliomas) and WHO grade IV refer to glioblastoma (GBM) and gliosarcoma [1]. Treatment options of gliomas include surgery, radiotherapy and chemotherapy. Although there is a standard treatment for glioblastoma – the most common and most aggressive type of gliomas – that includes radiotherapy with concurrent temozolomide followed by adjuvant temozolomide [2], there is no established standard treatment for less aggressive (lower grade) gliomas. In addition, the prognosis for glioblastoma continues to be poor. There is a desperate need for novel effective treatments for these devastating tumors. The accumulated wealth of knowledge about the molecular alterations involved in gliomagenesis and the increasing availability of novel molecularly targeted therapeutics may provide more effective treatment modalities. In this review, we discuss the most common alterations in the molecular pathways and the published clinical trials involving molecularly targeted therapies for gliomas.
Therapeutic Molecular Targets Introduction Cell Surface Molecular Targets Gliomas are the most frequent central nervous system (CNS) primary tumors, constituting more than 50 % of all primary CNS tumors. The World Health Organization (WHO) classified gliomas into four grades according to histopathology.
This article is part of the Topical Collection on Neuro-oncology M. A. Hamza (*) : M. Gilbert The University of Texas MD Anderson Cancer Center, Houston, TX, USA e-mail: [email protected] M. Gilbert e-mail: [email protected]
Epidermal Growth Factor Receptor (EGFR) EGFR is a member of the ErbB family, which consists of four receptors: HER1/EGFR, HER2, HER3 and HER4 [3]. EGFR is a 170 –kDa receptor tyrosine kinase that is formed of three domains: the extracellular domain, the transmembrane domain and the intracellular domain that contains the tyrosine kinase. Phosphorylation of the tyrosine kinase domain activates several signaling pathways, such as phosphatidylinositol 3’-kinase (PI3K)/AKT/mTOR, and Ras/mitogenactivated protein kinase (MAPK) [4]. Approximately 50 % of GBMs have amplification of EGFR, and overexpression of
379, Page 2 of 14
EGFR is common in malignant gliomas independent of amplification status [5]. The mutant receptor EGFRvIII has a deletion of exons 2-7 that causes a defect in the extracellular ligand-binding domain that results in constitutive activation of the receptor [6]. In addition, EGFRvIII may be an independent prognostic factor for poor survival outcome [7, 8]. Activation of EGFR pathways results in biological processes contributing to gliomagenesis including cell proliferation, angiogenesis, migration and survival. In addition, EGFR overexpression in GBM is associated with resistance to radiation therapy [9]. Platelet-Derived Growth Factor Receptor (PDGFR) The PDGF family signal through the alpha and beta PDGF receptor tyrosine kinases. The binding of the ligands to the extracellular domain of the receptor induces dimerization and cross-tyrosine phosphorylation of the intracellular domains. This results in the activation of several pathways including MAPK, PI3K, Jak family kinase, Src family kinase and phospholipase C-gamma. Approximately one- third of glioblastoma show overexpression of PDGFR-alpha [10]. Overexpression of PDGFR may be an important alteration in the transformation of low-grade gliomas to malignant gliomas [11]. In addition, analyses by the Cancer Genome Atlas Research Network showed that the proneural subtype of glioblastoma is characterized by aberrations of the PDGFR-alpha pathway, in addition to isocitrate dehydogenase-1 (IDH1) mutations [12]. Moreover, PDGFRs are involved in angiogenesis [13]. Vascular Endothelial Growth Factor (VEGF) VEGF is an important factor involved in neoangiogenesis which a characteristic of GBM [14]. Expression of VEGF is stimulated by hypoxia, acidosis, and growth factors such as PDGF, EGF, c-kit and hepatocyte growth factor (HGF). Binding of VEGF to its receptors VEGFR-1 and VEGFR-2 leads to phosphorylation of tyrosine kinase and activation of downstream signaling pathway including PI3K/Akt/PBK and Ras/MAPK [15]. The effects of VEGF include endothelial cell proliferation, cell migration, extracellular matrix degradation, and expression of proangiogenic factors including plasminogen activator inhibitor-1, urokinase-type plasminogen activator and matrix metalloproteinase-1 [16]. Integrins Integrins are heterodimeric cell surface adhesion receptors that function as receptors for extracellular matrix proteins including laminins, collagens, fibronectin, and vitronectin [17]. Binding of the ligand to the extracellular domain of the integrin receptor, which consists of two non-covalently associated alpha and beta subunits, results in activation of a
Curr Oncol Rep (2014) 16:379
signaling pathway involved in proliferation, migration, cell adhesions, differentiation and survival [18]. The integrins αvβ3 and αvβ5 are involved in the angiogenesis and tumor progression and are expressed in multiple malignancies including gliomas [19]. Intracellular Effectors/Pathways PI3K/AKT/mTOR Pathways PI3K is a serine / threonine kinase the activation of which results in phosphorylation and activation of downstream effectors including Akt and PBK that regulate cell growth, proliferation and apoptosis [20]. PI3K is activated by several receptor tyrosine kinases, integrins, and activated Ras. Akt is activated in approximately 70 % of GBM, in association with loss of PTEN (which leads to constitutive activation of the PI3K pathway) and/or activation of EGFR and PDFR tyrosine kinases [21]. Alteration of PTEN expression is present in 2040 % of GBM and is associated with a worse prognosis, and a mammalian target of rapamycin (mTOR) was identified as a critical downstream effector in PTEN/Akt signaling [22]. In addition, mTOR is also activated by Ras pathway, and activated mTOR activates ribosomal S6 kinase and inhibits the eukaryotic initiation factor 4E-binding protein-1, which is required for progression from G1 to S phase [7]. Protein Kinase C (PKC) Astrocytoma cells overexpress PKC, and the level of PKC activity was found to correlate with proliferation of astrocytoma cells [23]. PKC is involved in the downstream signaling of several growth factors that stimulates glioma cell proliferation including PDGF and EGF [24]. Activated PKC induces phosphorylation and activation of other downstream signaling effectors including Ras, Raf and MAPK [25]. Mitogen-Activated Protein Kinase (MAPK) Pathway The MAPK pathway involves activation of several protein kinases including Ras, Raf, Mek and Erk. Activation of Ras, a small guanine triphosphate-binding protein, results in activation of Raf, a serine/threonine kinase, which phosphorylates and activates MEK, and MEK subsequently phosphorylates and activates MAPK (also known as ERK) [26, 27]. These kinases activate downstream effectors that regulate transcription, translation and cytoskeletal rearrangement. Gliomas often have increased Ras activity as a result of mutation or amplification that result in activation of upstream growth factor receptors [28]. Farnesylation was found to be the rate–limiting step in Ras maturation [29]. Activation of Erk was found to correlate with poor outcome in GBM patients [30].
Curr Oncol Rep (2014) 16:379
Src and Src-Family Kinases (SFKs) Src and SFKs are effectors in multiple signaling pathways that regulate different aspects of tumor invasion and metastasis including proliferation, cell growth, adhesion, migration and invasion. Src and FYN (an SFK) were found to mediate EGFR and EGFRvIII signaling in a rodent GBM model [31]. Src inhibition decreases GBM cell viability and migration in vitro and decreased growth in vivo [32]. Src and SFKs activation and SFKs overexpression were reported in GBM cell lines and GBM patients [31]. Hepatocyte Growth Factor Receptor (c-MET) c-MET is a receptor tyrosine kinase for the hepatocyte growth factor, and aberrant signaling by the MET receptors and its potential role in tumor genesis has been reported [33]. In a study of 62 glioblastoma samples, c-MET overexpression was detected in 29 % of patients, and was associated with shorter overall survival when compared to those patients with little or no c-MET expression [34]. Other Molecular Targets
Page 3 of 14, 379
experimental approach for treatment of malignant glioma [40]. Death-receptor ligand activation may have an inhibiting effect on invasion, as demonstrated using anti-CD95 antibody treatment of mouse glioblastoma models [41]. Heat-Shock Proteins (HSPs) HSPs are protein chaperones that are overexpressed in several malignancies including gliomas [42]. HSPs are involved in the stability and activity of several proteins that stimulate growth, inhibit apoptosis, and promoting cell survival [43]. Inhibitors of HSPs may have a potential effect on potentiating signaling modulators and response to chemotherapy in gliomas [44]. Poly [ADP-Ribose] Polymerase (PARP) PARP is a DNA repair enzyme that is highly expressed in several types of cancer, and is thought to be implicated in the resistance of tumors to DNA damaging anticancer agents and radiotherapy [45]. PARP-1 is found to be expressed in the nuclei of GBM cells but not in normal brain tissue [46]. PARP inhibitors, in combination with DNA damaging agents may have a potential role in the treatment of gliomas.
Histone Deacetylases Nucleosomes are units of DNA organized by histone proteins. The acetylation and deacetylation (by histone deacetylases or HDACs) of the histone proteins may play an important role in the epigenetic modification of gene expression [35]. HDACs cause deacetylation of histones and condensation of the nucleosomes, which restricts access to the DNA [36]. Malignant gliomas have altered histone processing, and it is possible that HDAC inhibitors may increase the expression of certain genes that prevent or slow growth of tumors through mechanisms including induction of differentiation, cell cycle arrest and apoptosis [36, 37]. The Proteasome The proteolytic cellular functions of the proteasome include the cell cycle, inflammation, protein homeostasis and apoptosis [38]. Proteasome inhibitors may induce cell growth arrest and apoptosis and possibly decrease resistance to chemotherapy. Inhibition of proteasome activity may disrupt the degradation of proapoptotic proteins and enhance the degradation of NF-κB, which counteracts apoptosis [39]. Death Receptor Apoptosis can be induced through the activation of death receptors including Fas, TNFαR, DR3, DR4, and DR5 by their respective ligands. Death-receptor targeting has been an
Clinical Trials Involving Molecular Targeting Therapy for Gliomas Molecularly-targeted therapies are currently the focus of clinical research in primary brain tumors. The number of published clinical trials involving molecular-targeting agents has exceeded one hundred and is increasing (Tables 1 and 2). These publications started as early as twenty years ago with a single trial investigating the outcome of radiolabeled antiEGFR monoclonal antibodies in malignant astrocytoma [119]. The last several years have seen a dramatic increase in the number of trials with molecularly-targeted therapies for gliomas, with more than 20 trials of targeted agent-based clinical trials published in 2012. The most common molecular targets in early trials with single-target agents were inhibitors of EGFR and EGFRvIII, and inhibitors of VEGF and VEGFR. More recently, agents targeting different receptors such as integrins, or those inhibiting downstream signaling effectors such as Ras, MAPK and mTOR were studied more frequently in trials. However, with the exception of some trials with agents inhibiting EGFRvIII, molecular profile-based stratification of patients or analysis of outcome was not done in these trials. Single agent/single-target therapies were the most commonly investigated in glioma trials for many years; however, in the last few years this trend has reversed in favor of agents targeting multiple receptors or downstream effectors. In 2012, the ratio of the number of trials investigating multiple-target
Bevacizumab
Romidepsin
AMG 102 (rilotumumab) Trabedersen
VEGF
HDACs
HGF/SF
Cediranib
Cilengitide
anti-EGFR (125)I-mAb 425 Bortezomib
Enzastaurin
Enzastaurin
Integrins v3-v5
EGFR
Proteasome
PKC-beta
PKC-beta
Gefitinib
EGFR
VEGFR1, 2,3
Everolimus
Erlotinib
mTOR
EGFR
Tipifarnib
Temsirolimus
Farnesyl transferase
mTOR
TGF-β2
Bevacizumab
VEGF
Bevacizumab
Cilengitide
TLN-4601
Ras-MAPK
VEGF
Enzastaurin
Everolimus
mTOR
PKC-beta
Enzastaurin
PKC-beta
Integrins v3-v5
Vorinostat
Bevacizumab
Erlotinib
EGFR
HDACs
Dasatinib
SRC
VEGF
Everolimus
Gefitinib
mTOR
EGFR
Agents
Target
Enzastaurin
Enzastaurin, temozolomide, RT
Bortezomib
Cilengitide, temozolomide, RT anti-EGFR (125)I-mAb 425
Cediranib
Gefitinib
Erlotinib
Temsirolimus, temozolomide, RT Everolimus, temozolomide, RT
Tipifarnib
Trabedersen
AMG 102 (rilotumumab)
Bevacizumab, carboplatin, irinotecan Bevacizumab, temozolomide, RT, irinotecan Romidepsin
Cilengitide
Bevacizumab, carboplatin, irinotecan Enzastaurin, temozolomide
TLN-4601
Everolimus, temozolomide
Enzastaurin, temozolomide
Bevacizumab, irinotecan,
Vorinostat, temozolomide
Erlotinib
Dasatinib, CCNU
Gefitinib, RT
Everolimus, temozolomide, RT
Regimen
Table 1 Published clinical trials with single-target agents
I/II
I
I
II
I/II
II
II
II
I
I
I
IIb (RC)
II
I/II
II
II
II
II
II
II
I
I
II
I
I/II
I/II
I/II
I
Phase
Recurrent high-grade glioma
Newly diagnosed GBM
Recurrent malignant glioma
Newly diagnosed GBM
Newly diagnosed GBM
Recurrent GBM
Newly diagnosed GBM
Recurrent GBM (first relapse)
Newly diagnosed GBM
Newly diagnosed GBM
Recurrent/refractory high-grade glioma Newly diagnosed GBM
Recurrent GBM
Recurrent malignant glioma
Newly diagnosed GBM
Recurrent GBM (bev-resistant)
Recurrent GBM
Newly diagnosed GBM
Recurrent GBM (bev-naïve)
Newly diagnosed or recurrent GBM Newly diagnosed and recurrent GBM First recurrence of GBM
Recurrent primary brain tumors
High-grade gliomas
Recurrent/refractory GBM or AA
Recurrent GBM
Newly diagnosed GBM
Newly diagnosed GBM
Disease status
118
12
66
192
52
31
98
40
18
25
51
145
60
8/35
75
25
30
66
40
20
32
28
85
59
11
26
31/147
25
MTD 70 mg/week
[69]
[68]
[67]
[66]
DLTs thrombosis, thrombocytopenia, hemorrhage. RR 25 %, PFS6 7 % in GBM and 16 % in AG
MTD 2.5 mg/m2 in +EIASD and 1.7 mg/m2 in -EIASD patients. DLTs thrombocytopenia, MTD 250 mg daily
OS 15.7 months, 2-year OS 25.5 %
[74]
[73]
[72]
[71]
PFS6 69 %, PFS12 33 %, PFS 8 months, OS 16.1 months [70]
PFS6 25.8 %, RR 56.7 %.
PFS at 1 year 16 %, OS at 1 year 54 %
RR 6.3 %, PFS6 20 %, OS 9.7 months
[65]
[64]
[63]
Superior safety of trabedersen 10 μM when compared to trabedersen 80 μM and standard chemotherapy MTD 300 mg bid DLTs 25 % of grade 4/5 infections
[62]
[61]
[60]
[59]
[58]
[57]
[56]
[55]
[54]
[53]
[52]
[51]
[50]
[49]
[48]
[47]
Ref.
RR 0 %, PFS 4.3 weeks, OS 5.4 months
PFS 8 weeks, OS 34 weeks
PFS 14.2 months, OS 21.2 months
PFS6 16 %, OS 5.8 months
PFS6 12 %, drug detected in tumor specimen.
PFS 36 weeks, OS 74 weeks
PFS6 46.5 %, OS 8.3 months
PFS6 0 % , RR 0 %*
MTD everolimus 10 mg daily
MTD 500 mg daily
RR: GBM 25 %, AG 21 %, none in WHO grade II
DLTs: rash 90 %, diarrhea 60 %. PFS 1.9 months, OS 6.9 months MTD 500 mg daily
DLTs 38 %, PFS 1.3 months, PFS6 7.7 %
MTD 500 mg daily, OS 11.5 months
MTD 10 mg daily
No. of Outcome patients
379, Page 4 of 14 Curr Oncol Rep (2014) 16:379
Enzastaurin or lomustine
Erlotinib, temozolomide, RT
Bevacizumab
Cilengitide
Bevacizumab
Enzastaurin
Erlotinib
Bevacizumab
EGFRvIII-targeted dendritic cell-based vaccine Bevacizumab
Talampanel
Integrins v3-v5
VEGF
PKC-beta
EGFR
VEGF
EGFRvIII
Bortezomib, temozolomide, RT Erlotinib, temozolomide, RT Cilengitide Erlotinib, temozolomide, RT
Bevacizumab
Bortezomib
Erlotinib
Cilengitide
Erlotinib
Perillyl alcohol
VEGF
Proteasome
EGFR
Integrins v3-v5
EGFR
Ras-MAPK
Perillyl alcohol
Bevacizumab, irinotecan
Vorinostat
Lapatinib
Lapatinib
Vorinostat
HDACs
Bevacizumab: alone or plus irinotecan, Talampanel, temozolomide, RT
I/II
I/II
II (R)
II
I
II
II
I/II
II
II (R)
I
EGFRvIII-targeted dendritic cell-based vaccine
AMPA glutamatergic receptor EGFR/ErbB2
VEGF
II
II
III
II
II
II
II
II
Bevacizumab, etoposide
Bevacizumab
EGFRvIII-targeted peptide vaccine Bevacizumab, temozolomide, RT Bevacizumab, temozolomide (daily) Cilengitide, temozolomide, RT
VEGF
VEGF
I
II
Phase
Bevacizumab, temozolomide II or etoposide Bevacizumab, temozolomide, RT II
EGFRvIII-targeted peptide vaccine Bevacizumab
Bevacizumab
VEGF
Erlotinib
Bevacizumab
Erlotinib
EGFR
Erlotinib
VEGF
Erlotinib
EGFR
Regimen
EGFRvIII
Agents
Target
Table 1 (continued)
70
23
32
96
Recurrent malignant glioma
Newly diagnosed GBM
Recurrent GBM
Newly diagnosed and recurrent high-grade tumors Newly diagnosed GBM
Recurrent GBM
Recurrent GBM
Recurrent GBM
Newly diagnosed GBM
Recurrent GBM
Newly diagnosed GBM (EGFRvIII expressing)
Recurrent malignant glioma
Newly diagnosed GBM
Recurrent glioblastoma
Recurrent malignant glioma
Newly diagnosed GBM
Recurrent GBM
37
97
81
65
27
48
66
24
72
167
12
59
27
266
31
112
32
PFS6 was 48.2 % for GBM, 60 % for AA and 66.6 % for AO
PFS6 15 % and OS 9.9 months in patients received 2000 mg OS 15.3 months
OS 19.3 months
No DLTS with 1.3 mg/m2
PFS 16 weeks, PFS6 29 %, OS 31 weeks
PFS6 17.3 %, OS 5.7 months
RR 0 %, no DLTs with 1500 mg bid*
PFS6 42.6 % and 50.3 %,, RR 28.2 % and 37.8 %, and OS 9.2 months and 8.7 months, respectively OS 18.3 months, 24-month OS 41.7 %
PFS6, RR and OS were 44.4 % and 40.6 %, 37 % and 22 %, and 44.4 and 63.1 weeks for GBM and AG, respectively MTD not reached, PFS 6.8 months, OS 18.7 months
PFS6 33.9 %, PFS 3.3 months, OS10.5 months, 1-year OS 34.5 %, RR27.6 % PFS and OS were 1.5 months and 1.6 months, and 6.6 months and 7.1 months for Enzastaurin and lomustine, respectively PFS 2.8 months, OS 8.6 months*
OS 19.7 months
PFS6 85 %, PFS12 51 %, 12 and 24 months OS 85.1 % and 42.5 % PFS6 18.8 %, PFS 15.8 weeks, OS 37 weeks.
PFS6 67 %, OS 26 months
PFS 13.6 months, OS 19.6 months
PFS6 4.4 %, PFS 7.3 weeks
PFS6 and PFS in recurrent GBM 3 % and 2 months, in recurrent AG 27 % and 2 months, 12-month OS was 57 % in newly diagnosed GBM MTD 650 mg daily, DLT rash
No. of Outcome patients
Newly diagnosed GBM (EGFRvIII 21 expressing) Newly diagnosed GBM 51
Newly diagnosed GBM
Newly diagnosed GBM and recurrent malignant glioma and meningiomas Recurrent GBM (bev-resistant)
Newly diagnosed GBM and recurrent malignant glioma
Disease status
[97]
[96]
[95]
[94]
[93]
[92]
[91]
[90]
[89]
[88]
[87]
[86]
[85]
[84]
[83]
[82]
[81]
[80]
[79]
[78]
[77]
[76]
[75]
Ref.
Curr Oncol Rep (2014) 16:379 Page 5 of 14, 379
Gefitinib
Tipifarnib
Gefitinib
Tipifarnib
VEGF
Farnesyl transferase
EGFR
Farnesyl transferase
anti-EGFR (125)I-mAb 425
Recurrent malignant glioma
High-grade gliomas
Newly diagnosed GBM
Recurrent GBM
Recurrent high-grade glioma
Recurrent GBM (PTEN-deficient)
Newly diagnosed GBM
Recurrent malignant glioma
Recurrent GBM
Newly diagnosed GBM
Disease status
II
I/II
I/II
II
II
I
II
II
I
I/II
I
Newly diagnosed high-grade astrocytoma Malignant astrocytoma
Recurrent malignant glioma
Recurrent and progressive GBM
Recurrent GBM
Malignant glioma
Recurrent GBM
Recurrent GBM
Newly diagnosed high-grade glioma Stable or progressive malignant glioma
Newly diagnosed GBM
III (RCD) Newly diagnosed GBM
II
II
I
II
I
I
II
I
II
II
Phase
25
59
16
44
57
41
65
43
83
29
20
162
89
28
13
35
11
14
10
25
43
28
1-year OS 60 %, OS 15.6 months
No DLTs, 1-year OS 58 %, OS 13.5 months
PFS6 39 %, PFS 17 weeks, OS 45 weeks, 12-month PFS 16 % MTD 200 mg 3 times /week for 4 weeks. PFS3 0 %
RR 19.5 %, RR 44.4 % in patients with low level of phosphorylated PKB/Akt PFS6 13 %, PFS 8.1 weeks, OS 39.4 weeks
RR 36 %, PFS6 7.8 %, PFS 2.3 months, OS 4.4 months
PFS6: 9.1 % in AG, 11.9 % in GBM, 16.7 % in GBM not receiving EIAED OS 37.9 weeks for placebo and 42.9 weeks for marimastat MTD not reached at 150 mg daily in non-EIAED patients and 200 mg daily in EIAED patients. PFS 26 weeks, OS 55 weeks No DLTs, RR 37.9 %, OS 17.7 months in GBM, OS not reached in AG MTD: erlotinib alone 200 mg daily for non-EIAED patient and 500 mg daily for EIAED patients. Erlotinib plus temozolomide 450 mg daily for EIAED patients. PFS6 10.5 % PFS6 3.5 %, PFS 9 weeks
PFS6 14.3 %, PFS 8.4 weeks, OS 24.6 weeks
MTD 200 mg daily, OS 12 months
MTD 3 mg of nimotuzumab labeled with 10 mCi of (188)Re PFS6 46 %, 6-month OS 77 %.
Tumor cell proliferation decreased in 50 % of patients
Toxicity: DVT, PE.
MTD 70 mg daily, OS 6 months
PFS 9 weeks, PFS6 14 %, OS 30 weeks
OS 7.7 months*
No. of Outcome patients
[119]
[118]
[117]
[116]
[115]
[114]
[113]
[112]
[111]
[110]
[109]
[108]
[107]
[106]
[105]
[104]
[103]
[102]
[101]
[100]
[99]
[98]
Ref.
*Early termination
AA: anaplastic astrocytoma, AG: anaplastic glioma, GBM: glioblastoma, RR:response rate, EIAED: enzyme-inducing anti-epileptic drugs, MTD: maximum tolerated dose, DLT: dose-limiting toxicity, RR:response rate, PFS: progression free survival, PFS6: 6-month progression free survival, PFS12:12-month progression free survival, OS: overall survival, R: randomized, RC: randomized and placebocontrolled, RCD: randomized, placebo-controlled and double-blind
EGFR
anti-EGFR (125)I-mAb 425
EMD 55,900
anti-EGFR (125)I-mAb 425 anti-EGFR (125)I-mAb 425
EMD 55,900
EGFR
Marimastat, temozolomide
Gefitinib
Marimastat
Erlotinib alone or with temozolomide Gefitinib
EGFR
Erlotinib
EGFR
Temsirolimus
Temsirolimus
Erlotinib alone or with temozolomide
Matrix metallo-protease EGFR
Temsirolimus
Temsirolimus
Erlotinib
EGFR
mTOR
Nimotuzumab
EGFR
mTOR
Erlotinib, RT
Erlotinib
EGFR
Nimotuzumab, RT
Marimastat
Matrix metallopr-otease Marimastat
Tipifarnib
Tipifarnib, RT
Rapamycin
Bevacizumab, temozolomide, RT Rapamycin
Nimotuzumab Nimotuzumab labeled with labeled with 188 Re 188 Re Bevacizumab Bevacizumab, irinotecan
Bevacizumab
VEGF
Atrasentan
EGFR
Atrasentan
Endothelin-A receptor
Erlotinib, carboplatin
Tipifarnib (neoadjuvant)
Regimen
mTOR
Tipifarnib
Erlotinib
Farnesyl transferase
EGFR
Agents
Target
Table 1 (continued)
379, Page 6 of 14 Curr Oncol Rep (2014) 16:379
Sorafenib, temsirolimus Sunitinib Thalidomide, RT
Bevacizumab, erlotinib
Vandetanib
Sorafenib, temsirolimus
Sunitinib
VEGF, EGFR
VEGFR2/EGFR
II II
Erlotinib, Sorafenib Nintedanib
Sunitinib Bevacizumab, everolimus, temozlolmide, RT AEE788 Vorinostat, bortezomib Thalidomide, irinotecan
Sunitinib
Bevacizumab, everolimus
AEE788
Vorinostat, bortezomib
VEGFR/PDGFR/ c-kit/FLT3 VEGF, mTOR
EGFR/ErbB/VEGFR2
HDACs, proteasome
Cetuximab, bevacizumab
EGFR, VEGF
Pazopanib
Vandetanib
Vatalanib
VEGFR/c-kit/ PDGFR
VEGFR2/EGFR
VEGFR/PDGFR/c-kit
VEGF, bFGF, HGF, IL-8 ABT-510
Bevacizumab, Erlotinib
Sorafenib
Vatalanib
Thalidomide
VEGF/bFGF
VEGF, EGFR
Vatalanib, temozolomide, RT
Aflibercept
RAF/VEGFR/PDGFR
Aflibercept
Sunitinib
VEGFR/PDGFR/ c-kit/FLT3 VEGF, placental growth factor VEGFR/PDGFR/c-kit
Vandetanib, temozolomide, RT Vatalanib, temozolomide, RT
Pazopanib
Cetuximab, bevacizumab, irinotecan ABT-510, temozolomide, RT
Sorafenib, TMZ
Thalidomide, temozolomide, isotretinoin,celecoxib Bevacizumab, Erlotinib
Vorinostat, bevacizumab, irinotecan Sunitinib, irinotecan
Thalidomide
Vorinostat, bevacizumab
VEGF/bFGF
HDACs, VEGF
Erlotinib, sirolimus
Thalidomide
Erlotinib, sirolimus
EGFR, mTOR
I/II
I
II
I
II
II
II
I
I
II
I
I
II
II
I
II
II
I
II
II
I/II
Bevacizumab or bevacizumab II plus Erlotinib Vandetanib I/II
I/II
II
II
34/41
13
43
Recurrent GBM
25
89
63
13/18
15/64
10
19
39
37
64
68
19 54
Newly diagnosed GBM
Newly diagnosed GBM
Recurrent GBM
Newly diagnosed GBM
Recurrent GBM
Newly diagnosed GBM
20
13
35
23
43
47
Recurrent malignant glioma 57
Newly diagnosed GBM
Newly diagnosed GBM
Recurrent malignant glioma 58
Recurrent malignant glioma 25
Recurrent GBM
Recurrent AG
Recurrent GBM
Recurrent GBM
Newly diagnosed GBM
Recurrent malignant gliomas 30
Recurrent malignant gliomas 19
Newly diagnosed GBM
Recurrent GBM
Recurrent GBM
Recurrent AG/GBM
Recurrent GBM
[139]
[138]
[137]
[136]
[135]
[134]
[133]
[132]
[131]
[130]
[129]
[128]
[127]
[126]
[125]
[124]
[123]
[122]
[121]
[120]
Ref.
[143]
[142]
[145]
MTD 1000 mg daily*
[147]
MTD 100 mg daily, DLTs GI bleeding, thrombocytopenia, neutropenia [146]
PFS 12 weeks, PFS6 3 %, OS 35 weeks
MTD not reached with 200 mg daily, PFS 45.9 weeks, OS 64.4 weeks. [144]
RR 34 %, PFS6 30 %, OS 29 weeks
PFS 6 months, 1-year PFS 16 %, OS 12 months
PFS6 and OS: GBM 28 % and 42 weeks, and AG 44 % and 71 weeks [141]
DLTs fatigue, rash, neutropenia. OS 20 months, 2-year survival 40 %. [140]
PFS6 GBM 7.7 % and AG 25 %. RR 25 %. PFS GBM12 weeks, AG 24 weeks MTD not reached
MTD sunitinib 50 mg daily, PFS6 24 %, RR4%
MTD vorinostat 400 mg days 1-7 and 15-21.
PFS6 36 %, PFS 13 weeks, OS 62 weeks
PFS6 0 %, PFS 1.5 months, OS 3.2 months*
DLTs proteinuria, diarrhea, hepatotoxicity; RR 17 %*
PFS6 and OS were 21.5 % and 12.1 months for AA and 16.7 % and 12.6 months for GB PFS 11.3 months, OS 13.9 months
MTD erlotinib 150 mg daily, sirolimus 5 mg daily
MTD 400 mg daily, PFS6 and OS were 6.5 % and 6.3 months in GBM and 7 % and 7.6 months in AG MTD sorafenib 800 mg daily and temsirolimus 25 mg weekly. PFS6 0 %, PFS 8 weeks* PFS6 and OS were 10.4 % and 9.4 months in the bev-naïve and 0 % and 4.4 months in the bev-resistant Median survival 10 months
RR 70 %, 6-mo nth PFS 70 %, PFS 8 months, OS 9.5 months
Stable disease 12 %, PFS 1 month, OS 6 months*
OS 5.7 months, 6-month PFS 14 %
RR 5 % , MTD not reached*
RR 0 %, PFS 8 weeks, OS 15 weeks*
6-month PFS 26 %, OS 7,4 months*
No. of Outcome patients
Recurrent/progressive GBM 18
Recurrent GBM
Recurrent GBM
Recurrent GBM
Phase Disease status
Pazopanib, Lapatinib
Temsirolimus, Bevacizumab
RAF/VEGFR/ PDGFR, mTOR VEGFR/PDGFR/ c-kit/FLT3 VEGF/bFGF
VEGFR/c-kit/ PDGFR, EGFR/ErbB EGFR, RAF/VEGFR/ Erlotinib, Sorafenib PDGFR VEGFR/FGFR/ PDGFR Nintedanib
Temsirolimus, bevacizumab Pazopanib, Lapatinib
Sorafenib, TMZ
Sorafenib
RAF/VEGFR/PDGFR
mTOR, VEGF
Regimen
Agents
Targets
Table 2 Published clinical trials for multiple-targets agents
Curr Oncol Rep (2014) 16:379 Page 7 of 14, 379
Imatinib, hydroxyurea
Imatinib
Imatinib
Imatinib
PDGFR/ c-kit/bcr-abl
PDGFR/ c-kit/bcr-abl
PDGFR/ c-kit/bcr-abl
Thalidomide
Imatinib
Thalidomide
Imatinib
Gefitinib, sirolimus
Imatinib
Thalidomide
Thalidomide
VEGF/bFGF
PDGFR/ c-kit/bcr-abl
VEGF/bFGF
PDGFR/ c-kit/bcr-abl
EGFR, mTOR
PDGFR/ c-kit/bcr-abl
VEGF/bFGF
VEGF/bFGF
Thalidomide
Thalidomide
Thalidomide , carmustine
Thalidomide, temozolomide, RT Thalidomide alone or with temozolomide Thalidomide
Imatinib, hydroxyurea
Gefitinib, sirolimus
Imatinib
Thalidomide, temozolomide
Thalidomide, cisplatin, temozolomide Imatinib, hydroxyurea
Lenalidomide
Lenalidomide, RT
Thalidomide, irinotecan
II
II
II
II
II
II
II
I
I/II
II
II
I
I
II
I
II
I
II
II
I
II
III
II
II
32
20
231
44
39
17
36
32
65
50
23
26
22
18
44
67
33
42 Recurrent high-grade glioma 39
Recurrent GBM
Recurrent high-grade glioma 40
Recurrent GBM
Newly diagnosed GBM
Newly diagnosed GBM
Recurrent GBM
Recurrent malignant glioma 34
Recurrent malignant glioma 50/55
Recurrent GBM
Recurrent AG
Malignant brain tumors
Recurrent brain tumors
Newly diagnosed malignant glioma Recurrent GBM
Newly diagnosed GBM
Newly diagnosed or recurrent GBM Newly diagnosed GBM
Recurrent GBM
[151]
[150]
[149]
[148]
Ref.
RR 6 %, 1-year OS 20.5 %
OS 31 weeks, 1-year OS 35 %
PFS 100 days, RR 24 %
OS and PFS 103 weeks and 36 weeks for thalidomide and temozolomide, and 63 weeks and 17 weeks for thalidomide. PFS 25 weeks, OS 36 weeks
PFS 22 weeks, OS 73 weeks
No DLTs with 1200 mg daily in non-EIAED patients. PFS6 3 % for GBM and 10 % in AG MTD: non- EIAED patients gefitinib 500 mg and sirolimus 5 mg daily, EIAED patients gefitinib 1000 mg and sirolimus 10 mg daily. DLTs: stomatitis, diarrhea, rash, thrombocytopenia. PFS6 27 %, PFS 14.4 weeks
RR 7 %, PFS6 24 %, PFS 15 weeks
PFS6 24 %, RR 10 %,
MTD 150 mg daily, DLTs thrombocytopenia and febrile neutropenia
MTD 20 mg/m2, PFS
NEURO-ONCOLOGY (M GILBERT, SECTION EDITOR)
Targeted Therapy in Gliomas Mohamed Ali Hamza & Mark Gilbert
# Springer Science+Business Media New York 2014
Abstract The survival outcome of patients with malignant gliomas is still poor, despite advances in surgical techniques, radiation therapy and the development of novel chemotherapeutic agents. The heterogeneity of molecular alterations in signaling pathways involved in the pathogenesis of these tumors contributes significantly to their resistance to treatment. Several molecular targets for therapy have been discovered over the last several years. Therapeutic agents targeting these signaling pathways may provide more effective treatments and may improve survival. This review summarizes the important molecular therapeutic targets and the outcome of published clinical trials involving targeted therapeutic agents in glioma patients. Keywords Malignant gliomas . Gliomas . Radiation therapy . Chemotherapeutic agents . Oncology . Neuro-oncology . Molecular targets . Glioma patients . Central nervous system (CNS) . Flioblastoma (GBM) . Anaplastic gliomas . Therapeutic agents
Malignant gliomas refer to WHO grade III (anaplastic gliomas) and WHO grade IV refer to glioblastoma (GBM) and gliosarcoma [1]. Treatment options of gliomas include surgery, radiotherapy and chemotherapy. Although there is a standard treatment for glioblastoma – the most common and most aggressive type of gliomas – that includes radiotherapy with concurrent temozolomide followed by adjuvant temozolomide [2], there is no established standard treatment for less aggressive (lower grade) gliomas. In addition, the prognosis for glioblastoma continues to be poor. There is a desperate need for novel effective treatments for these devastating tumors. The accumulated wealth of knowledge about the molecular alterations involved in gliomagenesis and the increasing availability of novel molecularly targeted therapeutics may provide more effective treatment modalities. In this review, we discuss the most common alterations in the molecular pathways and the published clinical trials involving molecularly targeted therapies for gliomas.
Therapeutic Molecular Targets Introduction Cell Surface Molecular Targets Gliomas are the most frequent central nervous system (CNS) primary tumors, constituting more than 50 % of all primary CNS tumors. The World Health Organization (WHO) classified gliomas into four grades according to histopathology.
This article is part of the Topical Collection on Neuro-oncology M. A. Hamza (*) : M. Gilbert The University of Texas MD Anderson Cancer Center, Houston, TX, USA e-mail: [email protected] M. Gilbert e-mail: [email protected]
Epidermal Growth Factor Receptor (EGFR) EGFR is a member of the ErbB family, which consists of four receptors: HER1/EGFR, HER2, HER3 and HER4 [3]. EGFR is a 170 –kDa receptor tyrosine kinase that is formed of three domains: the extracellular domain, the transmembrane domain and the intracellular domain that contains the tyrosine kinase. Phosphorylation of the tyrosine kinase domain activates several signaling pathways, such as phosphatidylinositol 3’-kinase (PI3K)/AKT/mTOR, and Ras/mitogenactivated protein kinase (MAPK) [4]. Approximately 50 % of GBMs have amplification of EGFR, and overexpression of
379, Page 2 of 14
EGFR is common in malignant gliomas independent of amplification status [5]. The mutant receptor EGFRvIII has a deletion of exons 2-7 that causes a defect in the extracellular ligand-binding domain that results in constitutive activation of the receptor [6]. In addition, EGFRvIII may be an independent prognostic factor for poor survival outcome [7, 8]. Activation of EGFR pathways results in biological processes contributing to gliomagenesis including cell proliferation, angiogenesis, migration and survival. In addition, EGFR overexpression in GBM is associated with resistance to radiation therapy [9]. Platelet-Derived Growth Factor Receptor (PDGFR) The PDGF family signal through the alpha and beta PDGF receptor tyrosine kinases. The binding of the ligands to the extracellular domain of the receptor induces dimerization and cross-tyrosine phosphorylation of the intracellular domains. This results in the activation of several pathways including MAPK, PI3K, Jak family kinase, Src family kinase and phospholipase C-gamma. Approximately one- third of glioblastoma show overexpression of PDGFR-alpha [10]. Overexpression of PDGFR may be an important alteration in the transformation of low-grade gliomas to malignant gliomas [11]. In addition, analyses by the Cancer Genome Atlas Research Network showed that the proneural subtype of glioblastoma is characterized by aberrations of the PDGFR-alpha pathway, in addition to isocitrate dehydogenase-1 (IDH1) mutations [12]. Moreover, PDGFRs are involved in angiogenesis [13]. Vascular Endothelial Growth Factor (VEGF) VEGF is an important factor involved in neoangiogenesis which a characteristic of GBM [14]. Expression of VEGF is stimulated by hypoxia, acidosis, and growth factors such as PDGF, EGF, c-kit and hepatocyte growth factor (HGF). Binding of VEGF to its receptors VEGFR-1 and VEGFR-2 leads to phosphorylation of tyrosine kinase and activation of downstream signaling pathway including PI3K/Akt/PBK and Ras/MAPK [15]. The effects of VEGF include endothelial cell proliferation, cell migration, extracellular matrix degradation, and expression of proangiogenic factors including plasminogen activator inhibitor-1, urokinase-type plasminogen activator and matrix metalloproteinase-1 [16]. Integrins Integrins are heterodimeric cell surface adhesion receptors that function as receptors for extracellular matrix proteins including laminins, collagens, fibronectin, and vitronectin [17]. Binding of the ligand to the extracellular domain of the integrin receptor, which consists of two non-covalently associated alpha and beta subunits, results in activation of a
Curr Oncol Rep (2014) 16:379
signaling pathway involved in proliferation, migration, cell adhesions, differentiation and survival [18]. The integrins αvβ3 and αvβ5 are involved in the angiogenesis and tumor progression and are expressed in multiple malignancies including gliomas [19]. Intracellular Effectors/Pathways PI3K/AKT/mTOR Pathways PI3K is a serine / threonine kinase the activation of which results in phosphorylation and activation of downstream effectors including Akt and PBK that regulate cell growth, proliferation and apoptosis [20]. PI3K is activated by several receptor tyrosine kinases, integrins, and activated Ras. Akt is activated in approximately 70 % of GBM, in association with loss of PTEN (which leads to constitutive activation of the PI3K pathway) and/or activation of EGFR and PDFR tyrosine kinases [21]. Alteration of PTEN expression is present in 2040 % of GBM and is associated with a worse prognosis, and a mammalian target of rapamycin (mTOR) was identified as a critical downstream effector in PTEN/Akt signaling [22]. In addition, mTOR is also activated by Ras pathway, and activated mTOR activates ribosomal S6 kinase and inhibits the eukaryotic initiation factor 4E-binding protein-1, which is required for progression from G1 to S phase [7]. Protein Kinase C (PKC) Astrocytoma cells overexpress PKC, and the level of PKC activity was found to correlate with proliferation of astrocytoma cells [23]. PKC is involved in the downstream signaling of several growth factors that stimulates glioma cell proliferation including PDGF and EGF [24]. Activated PKC induces phosphorylation and activation of other downstream signaling effectors including Ras, Raf and MAPK [25]. Mitogen-Activated Protein Kinase (MAPK) Pathway The MAPK pathway involves activation of several protein kinases including Ras, Raf, Mek and Erk. Activation of Ras, a small guanine triphosphate-binding protein, results in activation of Raf, a serine/threonine kinase, which phosphorylates and activates MEK, and MEK subsequently phosphorylates and activates MAPK (also known as ERK) [26, 27]. These kinases activate downstream effectors that regulate transcription, translation and cytoskeletal rearrangement. Gliomas often have increased Ras activity as a result of mutation or amplification that result in activation of upstream growth factor receptors [28]. Farnesylation was found to be the rate–limiting step in Ras maturation [29]. Activation of Erk was found to correlate with poor outcome in GBM patients [30].
Curr Oncol Rep (2014) 16:379
Src and Src-Family Kinases (SFKs) Src and SFKs are effectors in multiple signaling pathways that regulate different aspects of tumor invasion and metastasis including proliferation, cell growth, adhesion, migration and invasion. Src and FYN (an SFK) were found to mediate EGFR and EGFRvIII signaling in a rodent GBM model [31]. Src inhibition decreases GBM cell viability and migration in vitro and decreased growth in vivo [32]. Src and SFKs activation and SFKs overexpression were reported in GBM cell lines and GBM patients [31]. Hepatocyte Growth Factor Receptor (c-MET) c-MET is a receptor tyrosine kinase for the hepatocyte growth factor, and aberrant signaling by the MET receptors and its potential role in tumor genesis has been reported [33]. In a study of 62 glioblastoma samples, c-MET overexpression was detected in 29 % of patients, and was associated with shorter overall survival when compared to those patients with little or no c-MET expression [34]. Other Molecular Targets
Page 3 of 14, 379
experimental approach for treatment of malignant glioma [40]. Death-receptor ligand activation may have an inhibiting effect on invasion, as demonstrated using anti-CD95 antibody treatment of mouse glioblastoma models [41]. Heat-Shock Proteins (HSPs) HSPs are protein chaperones that are overexpressed in several malignancies including gliomas [42]. HSPs are involved in the stability and activity of several proteins that stimulate growth, inhibit apoptosis, and promoting cell survival [43]. Inhibitors of HSPs may have a potential effect on potentiating signaling modulators and response to chemotherapy in gliomas [44]. Poly [ADP-Ribose] Polymerase (PARP) PARP is a DNA repair enzyme that is highly expressed in several types of cancer, and is thought to be implicated in the resistance of tumors to DNA damaging anticancer agents and radiotherapy [45]. PARP-1 is found to be expressed in the nuclei of GBM cells but not in normal brain tissue [46]. PARP inhibitors, in combination with DNA damaging agents may have a potential role in the treatment of gliomas.
Histone Deacetylases Nucleosomes are units of DNA organized by histone proteins. The acetylation and deacetylation (by histone deacetylases or HDACs) of the histone proteins may play an important role in the epigenetic modification of gene expression [35]. HDACs cause deacetylation of histones and condensation of the nucleosomes, which restricts access to the DNA [36]. Malignant gliomas have altered histone processing, and it is possible that HDAC inhibitors may increase the expression of certain genes that prevent or slow growth of tumors through mechanisms including induction of differentiation, cell cycle arrest and apoptosis [36, 37]. The Proteasome The proteolytic cellular functions of the proteasome include the cell cycle, inflammation, protein homeostasis and apoptosis [38]. Proteasome inhibitors may induce cell growth arrest and apoptosis and possibly decrease resistance to chemotherapy. Inhibition of proteasome activity may disrupt the degradation of proapoptotic proteins and enhance the degradation of NF-κB, which counteracts apoptosis [39]. Death Receptor Apoptosis can be induced through the activation of death receptors including Fas, TNFαR, DR3, DR4, and DR5 by their respective ligands. Death-receptor targeting has been an
Clinical Trials Involving Molecular Targeting Therapy for Gliomas Molecularly-targeted therapies are currently the focus of clinical research in primary brain tumors. The number of published clinical trials involving molecular-targeting agents has exceeded one hundred and is increasing (Tables 1 and 2). These publications started as early as twenty years ago with a single trial investigating the outcome of radiolabeled antiEGFR monoclonal antibodies in malignant astrocytoma [119]. The last several years have seen a dramatic increase in the number of trials with molecularly-targeted therapies for gliomas, with more than 20 trials of targeted agent-based clinical trials published in 2012. The most common molecular targets in early trials with single-target agents were inhibitors of EGFR and EGFRvIII, and inhibitors of VEGF and VEGFR. More recently, agents targeting different receptors such as integrins, or those inhibiting downstream signaling effectors such as Ras, MAPK and mTOR were studied more frequently in trials. However, with the exception of some trials with agents inhibiting EGFRvIII, molecular profile-based stratification of patients or analysis of outcome was not done in these trials. Single agent/single-target therapies were the most commonly investigated in glioma trials for many years; however, in the last few years this trend has reversed in favor of agents targeting multiple receptors or downstream effectors. In 2012, the ratio of the number of trials investigating multiple-target
Bevacizumab
Romidepsin
AMG 102 (rilotumumab) Trabedersen
VEGF
HDACs
HGF/SF
Cediranib
Cilengitide
anti-EGFR (125)I-mAb 425 Bortezomib
Enzastaurin
Enzastaurin
Integrins v3-v5
EGFR
Proteasome
PKC-beta
PKC-beta
Gefitinib
EGFR
VEGFR1, 2,3
Everolimus
Erlotinib
mTOR
EGFR
Tipifarnib
Temsirolimus
Farnesyl transferase
mTOR
TGF-β2
Bevacizumab
VEGF
Bevacizumab
Cilengitide
TLN-4601
Ras-MAPK
VEGF
Enzastaurin
Everolimus
mTOR
PKC-beta
Enzastaurin
PKC-beta
Integrins v3-v5
Vorinostat
Bevacizumab
Erlotinib
EGFR
HDACs
Dasatinib
SRC
VEGF
Everolimus
Gefitinib
mTOR
EGFR
Agents
Target
Enzastaurin
Enzastaurin, temozolomide, RT
Bortezomib
Cilengitide, temozolomide, RT anti-EGFR (125)I-mAb 425
Cediranib
Gefitinib
Erlotinib
Temsirolimus, temozolomide, RT Everolimus, temozolomide, RT
Tipifarnib
Trabedersen
AMG 102 (rilotumumab)
Bevacizumab, carboplatin, irinotecan Bevacizumab, temozolomide, RT, irinotecan Romidepsin
Cilengitide
Bevacizumab, carboplatin, irinotecan Enzastaurin, temozolomide
TLN-4601
Everolimus, temozolomide
Enzastaurin, temozolomide
Bevacizumab, irinotecan,
Vorinostat, temozolomide
Erlotinib
Dasatinib, CCNU
Gefitinib, RT
Everolimus, temozolomide, RT
Regimen
Table 1 Published clinical trials with single-target agents
I/II
I
I
II
I/II
II
II
II
I
I
I
IIb (RC)
II
I/II
II
II
II
II
II
II
I
I
II
I
I/II
I/II
I/II
I
Phase
Recurrent high-grade glioma
Newly diagnosed GBM
Recurrent malignant glioma
Newly diagnosed GBM
Newly diagnosed GBM
Recurrent GBM
Newly diagnosed GBM
Recurrent GBM (first relapse)
Newly diagnosed GBM
Newly diagnosed GBM
Recurrent/refractory high-grade glioma Newly diagnosed GBM
Recurrent GBM
Recurrent malignant glioma
Newly diagnosed GBM
Recurrent GBM (bev-resistant)
Recurrent GBM
Newly diagnosed GBM
Recurrent GBM (bev-naïve)
Newly diagnosed or recurrent GBM Newly diagnosed and recurrent GBM First recurrence of GBM
Recurrent primary brain tumors
High-grade gliomas
Recurrent/refractory GBM or AA
Recurrent GBM
Newly diagnosed GBM
Newly diagnosed GBM
Disease status
118
12
66
192
52
31
98
40
18
25
51
145
60
8/35
75
25
30
66
40
20
32
28
85
59
11
26
31/147
25
MTD 70 mg/week
[69]
[68]
[67]
[66]
DLTs thrombosis, thrombocytopenia, hemorrhage. RR 25 %, PFS6 7 % in GBM and 16 % in AG
MTD 2.5 mg/m2 in +EIASD and 1.7 mg/m2 in -EIASD patients. DLTs thrombocytopenia, MTD 250 mg daily
OS 15.7 months, 2-year OS 25.5 %
[74]
[73]
[72]
[71]
PFS6 69 %, PFS12 33 %, PFS 8 months, OS 16.1 months [70]
PFS6 25.8 %, RR 56.7 %.
PFS at 1 year 16 %, OS at 1 year 54 %
RR 6.3 %, PFS6 20 %, OS 9.7 months
[65]
[64]
[63]
Superior safety of trabedersen 10 μM when compared to trabedersen 80 μM and standard chemotherapy MTD 300 mg bid DLTs 25 % of grade 4/5 infections
[62]
[61]
[60]
[59]
[58]
[57]
[56]
[55]
[54]
[53]
[52]
[51]
[50]
[49]
[48]
[47]
Ref.
RR 0 %, PFS 4.3 weeks, OS 5.4 months
PFS 8 weeks, OS 34 weeks
PFS 14.2 months, OS 21.2 months
PFS6 16 %, OS 5.8 months
PFS6 12 %, drug detected in tumor specimen.
PFS 36 weeks, OS 74 weeks
PFS6 46.5 %, OS 8.3 months
PFS6 0 % , RR 0 %*
MTD everolimus 10 mg daily
MTD 500 mg daily
RR: GBM 25 %, AG 21 %, none in WHO grade II
DLTs: rash 90 %, diarrhea 60 %. PFS 1.9 months, OS 6.9 months MTD 500 mg daily
DLTs 38 %, PFS 1.3 months, PFS6 7.7 %
MTD 500 mg daily, OS 11.5 months
MTD 10 mg daily
No. of Outcome patients
379, Page 4 of 14 Curr Oncol Rep (2014) 16:379
Enzastaurin or lomustine
Erlotinib, temozolomide, RT
Bevacizumab
Cilengitide
Bevacizumab
Enzastaurin
Erlotinib
Bevacizumab
EGFRvIII-targeted dendritic cell-based vaccine Bevacizumab
Talampanel
Integrins v3-v5
VEGF
PKC-beta
EGFR
VEGF
EGFRvIII
Bortezomib, temozolomide, RT Erlotinib, temozolomide, RT Cilengitide Erlotinib, temozolomide, RT
Bevacizumab
Bortezomib
Erlotinib
Cilengitide
Erlotinib
Perillyl alcohol
VEGF
Proteasome
EGFR
Integrins v3-v5
EGFR
Ras-MAPK
Perillyl alcohol
Bevacizumab, irinotecan
Vorinostat
Lapatinib
Lapatinib
Vorinostat
HDACs
Bevacizumab: alone or plus irinotecan, Talampanel, temozolomide, RT
I/II
I/II
II (R)
II
I
II
II
I/II
II
II (R)
I
EGFRvIII-targeted dendritic cell-based vaccine
AMPA glutamatergic receptor EGFR/ErbB2
VEGF
II
II
III
II
II
II
II
II
Bevacizumab, etoposide
Bevacizumab
EGFRvIII-targeted peptide vaccine Bevacizumab, temozolomide, RT Bevacizumab, temozolomide (daily) Cilengitide, temozolomide, RT
VEGF
VEGF
I
II
Phase
Bevacizumab, temozolomide II or etoposide Bevacizumab, temozolomide, RT II
EGFRvIII-targeted peptide vaccine Bevacizumab
Bevacizumab
VEGF
Erlotinib
Bevacizumab
Erlotinib
EGFR
Erlotinib
VEGF
Erlotinib
EGFR
Regimen
EGFRvIII
Agents
Target
Table 1 (continued)
70
23
32
96
Recurrent malignant glioma
Newly diagnosed GBM
Recurrent GBM
Newly diagnosed and recurrent high-grade tumors Newly diagnosed GBM
Recurrent GBM
Recurrent GBM
Recurrent GBM
Newly diagnosed GBM
Recurrent GBM
Newly diagnosed GBM (EGFRvIII expressing)
Recurrent malignant glioma
Newly diagnosed GBM
Recurrent glioblastoma
Recurrent malignant glioma
Newly diagnosed GBM
Recurrent GBM
37
97
81
65
27
48
66
24
72
167
12
59
27
266
31
112
32
PFS6 was 48.2 % for GBM, 60 % for AA and 66.6 % for AO
PFS6 15 % and OS 9.9 months in patients received 2000 mg OS 15.3 months
OS 19.3 months
No DLTS with 1.3 mg/m2
PFS 16 weeks, PFS6 29 %, OS 31 weeks
PFS6 17.3 %, OS 5.7 months
RR 0 %, no DLTs with 1500 mg bid*
PFS6 42.6 % and 50.3 %,, RR 28.2 % and 37.8 %, and OS 9.2 months and 8.7 months, respectively OS 18.3 months, 24-month OS 41.7 %
PFS6, RR and OS were 44.4 % and 40.6 %, 37 % and 22 %, and 44.4 and 63.1 weeks for GBM and AG, respectively MTD not reached, PFS 6.8 months, OS 18.7 months
PFS6 33.9 %, PFS 3.3 months, OS10.5 months, 1-year OS 34.5 %, RR27.6 % PFS and OS were 1.5 months and 1.6 months, and 6.6 months and 7.1 months for Enzastaurin and lomustine, respectively PFS 2.8 months, OS 8.6 months*
OS 19.7 months
PFS6 85 %, PFS12 51 %, 12 and 24 months OS 85.1 % and 42.5 % PFS6 18.8 %, PFS 15.8 weeks, OS 37 weeks.
PFS6 67 %, OS 26 months
PFS 13.6 months, OS 19.6 months
PFS6 4.4 %, PFS 7.3 weeks
PFS6 and PFS in recurrent GBM 3 % and 2 months, in recurrent AG 27 % and 2 months, 12-month OS was 57 % in newly diagnosed GBM MTD 650 mg daily, DLT rash
No. of Outcome patients
Newly diagnosed GBM (EGFRvIII 21 expressing) Newly diagnosed GBM 51
Newly diagnosed GBM
Newly diagnosed GBM and recurrent malignant glioma and meningiomas Recurrent GBM (bev-resistant)
Newly diagnosed GBM and recurrent malignant glioma
Disease status
[97]
[96]
[95]
[94]
[93]
[92]
[91]
[90]
[89]
[88]
[87]
[86]
[85]
[84]
[83]
[82]
[81]
[80]
[79]
[78]
[77]
[76]
[75]
Ref.
Curr Oncol Rep (2014) 16:379 Page 5 of 14, 379
Gefitinib
Tipifarnib
Gefitinib
Tipifarnib
VEGF
Farnesyl transferase
EGFR
Farnesyl transferase
anti-EGFR (125)I-mAb 425
Recurrent malignant glioma
High-grade gliomas
Newly diagnosed GBM
Recurrent GBM
Recurrent high-grade glioma
Recurrent GBM (PTEN-deficient)
Newly diagnosed GBM
Recurrent malignant glioma
Recurrent GBM
Newly diagnosed GBM
Disease status
II
I/II
I/II
II
II
I
II
II
I
I/II
I
Newly diagnosed high-grade astrocytoma Malignant astrocytoma
Recurrent malignant glioma
Recurrent and progressive GBM
Recurrent GBM
Malignant glioma
Recurrent GBM
Recurrent GBM
Newly diagnosed high-grade glioma Stable or progressive malignant glioma
Newly diagnosed GBM
III (RCD) Newly diagnosed GBM
II
II
I
II
I
I
II
I
II
II
Phase
25
59
16
44
57
41
65
43
83
29
20
162
89
28
13
35
11
14
10
25
43
28
1-year OS 60 %, OS 15.6 months
No DLTs, 1-year OS 58 %, OS 13.5 months
PFS6 39 %, PFS 17 weeks, OS 45 weeks, 12-month PFS 16 % MTD 200 mg 3 times /week for 4 weeks. PFS3 0 %
RR 19.5 %, RR 44.4 % in patients with low level of phosphorylated PKB/Akt PFS6 13 %, PFS 8.1 weeks, OS 39.4 weeks
RR 36 %, PFS6 7.8 %, PFS 2.3 months, OS 4.4 months
PFS6: 9.1 % in AG, 11.9 % in GBM, 16.7 % in GBM not receiving EIAED OS 37.9 weeks for placebo and 42.9 weeks for marimastat MTD not reached at 150 mg daily in non-EIAED patients and 200 mg daily in EIAED patients. PFS 26 weeks, OS 55 weeks No DLTs, RR 37.9 %, OS 17.7 months in GBM, OS not reached in AG MTD: erlotinib alone 200 mg daily for non-EIAED patient and 500 mg daily for EIAED patients. Erlotinib plus temozolomide 450 mg daily for EIAED patients. PFS6 10.5 % PFS6 3.5 %, PFS 9 weeks
PFS6 14.3 %, PFS 8.4 weeks, OS 24.6 weeks
MTD 200 mg daily, OS 12 months
MTD 3 mg of nimotuzumab labeled with 10 mCi of (188)Re PFS6 46 %, 6-month OS 77 %.
Tumor cell proliferation decreased in 50 % of patients
Toxicity: DVT, PE.
MTD 70 mg daily, OS 6 months
PFS 9 weeks, PFS6 14 %, OS 30 weeks
OS 7.7 months*
No. of Outcome patients
[119]
[118]
[117]
[116]
[115]
[114]
[113]
[112]
[111]
[110]
[109]
[108]
[107]
[106]
[105]
[104]
[103]
[102]
[101]
[100]
[99]
[98]
Ref.
*Early termination
AA: anaplastic astrocytoma, AG: anaplastic glioma, GBM: glioblastoma, RR:response rate, EIAED: enzyme-inducing anti-epileptic drugs, MTD: maximum tolerated dose, DLT: dose-limiting toxicity, RR:response rate, PFS: progression free survival, PFS6: 6-month progression free survival, PFS12:12-month progression free survival, OS: overall survival, R: randomized, RC: randomized and placebocontrolled, RCD: randomized, placebo-controlled and double-blind
EGFR
anti-EGFR (125)I-mAb 425
EMD 55,900
anti-EGFR (125)I-mAb 425 anti-EGFR (125)I-mAb 425
EMD 55,900
EGFR
Marimastat, temozolomide
Gefitinib
Marimastat
Erlotinib alone or with temozolomide Gefitinib
EGFR
Erlotinib
EGFR
Temsirolimus
Temsirolimus
Erlotinib alone or with temozolomide
Matrix metallo-protease EGFR
Temsirolimus
Temsirolimus
Erlotinib
EGFR
mTOR
Nimotuzumab
EGFR
mTOR
Erlotinib, RT
Erlotinib
EGFR
Nimotuzumab, RT
Marimastat
Matrix metallopr-otease Marimastat
Tipifarnib
Tipifarnib, RT
Rapamycin
Bevacizumab, temozolomide, RT Rapamycin
Nimotuzumab Nimotuzumab labeled with labeled with 188 Re 188 Re Bevacizumab Bevacizumab, irinotecan
Bevacizumab
VEGF
Atrasentan
EGFR
Atrasentan
Endothelin-A receptor
Erlotinib, carboplatin
Tipifarnib (neoadjuvant)
Regimen
mTOR
Tipifarnib
Erlotinib
Farnesyl transferase
EGFR
Agents
Target
Table 1 (continued)
379, Page 6 of 14 Curr Oncol Rep (2014) 16:379
Sorafenib, temsirolimus Sunitinib Thalidomide, RT
Bevacizumab, erlotinib
Vandetanib
Sorafenib, temsirolimus
Sunitinib
VEGF, EGFR
VEGFR2/EGFR
II II
Erlotinib, Sorafenib Nintedanib
Sunitinib Bevacizumab, everolimus, temozlolmide, RT AEE788 Vorinostat, bortezomib Thalidomide, irinotecan
Sunitinib
Bevacizumab, everolimus
AEE788
Vorinostat, bortezomib
VEGFR/PDGFR/ c-kit/FLT3 VEGF, mTOR
EGFR/ErbB/VEGFR2
HDACs, proteasome
Cetuximab, bevacizumab
EGFR, VEGF
Pazopanib
Vandetanib
Vatalanib
VEGFR/c-kit/ PDGFR
VEGFR2/EGFR
VEGFR/PDGFR/c-kit
VEGF, bFGF, HGF, IL-8 ABT-510
Bevacizumab, Erlotinib
Sorafenib
Vatalanib
Thalidomide
VEGF/bFGF
VEGF, EGFR
Vatalanib, temozolomide, RT
Aflibercept
RAF/VEGFR/PDGFR
Aflibercept
Sunitinib
VEGFR/PDGFR/ c-kit/FLT3 VEGF, placental growth factor VEGFR/PDGFR/c-kit
Vandetanib, temozolomide, RT Vatalanib, temozolomide, RT
Pazopanib
Cetuximab, bevacizumab, irinotecan ABT-510, temozolomide, RT
Sorafenib, TMZ
Thalidomide, temozolomide, isotretinoin,celecoxib Bevacizumab, Erlotinib
Vorinostat, bevacizumab, irinotecan Sunitinib, irinotecan
Thalidomide
Vorinostat, bevacizumab
VEGF/bFGF
HDACs, VEGF
Erlotinib, sirolimus
Thalidomide
Erlotinib, sirolimus
EGFR, mTOR
I/II
I
II
I
II
II
II
I
I
II
I
I
II
II
I
II
II
I
II
II
I/II
Bevacizumab or bevacizumab II plus Erlotinib Vandetanib I/II
I/II
II
II
34/41
13
43
Recurrent GBM
25
89
63
13/18
15/64
10
19
39
37
64
68
19 54
Newly diagnosed GBM
Newly diagnosed GBM
Recurrent GBM
Newly diagnosed GBM
Recurrent GBM
Newly diagnosed GBM
20
13
35
23
43
47
Recurrent malignant glioma 57
Newly diagnosed GBM
Newly diagnosed GBM
Recurrent malignant glioma 58
Recurrent malignant glioma 25
Recurrent GBM
Recurrent AG
Recurrent GBM
Recurrent GBM
Newly diagnosed GBM
Recurrent malignant gliomas 30
Recurrent malignant gliomas 19
Newly diagnosed GBM
Recurrent GBM
Recurrent GBM
Recurrent AG/GBM
Recurrent GBM
[139]
[138]
[137]
[136]
[135]
[134]
[133]
[132]
[131]
[130]
[129]
[128]
[127]
[126]
[125]
[124]
[123]
[122]
[121]
[120]
Ref.
[143]
[142]
[145]
MTD 1000 mg daily*
[147]
MTD 100 mg daily, DLTs GI bleeding, thrombocytopenia, neutropenia [146]
PFS 12 weeks, PFS6 3 %, OS 35 weeks
MTD not reached with 200 mg daily, PFS 45.9 weeks, OS 64.4 weeks. [144]
RR 34 %, PFS6 30 %, OS 29 weeks
PFS 6 months, 1-year PFS 16 %, OS 12 months
PFS6 and OS: GBM 28 % and 42 weeks, and AG 44 % and 71 weeks [141]
DLTs fatigue, rash, neutropenia. OS 20 months, 2-year survival 40 %. [140]
PFS6 GBM 7.7 % and AG 25 %. RR 25 %. PFS GBM12 weeks, AG 24 weeks MTD not reached
MTD sunitinib 50 mg daily, PFS6 24 %, RR4%
MTD vorinostat 400 mg days 1-7 and 15-21.
PFS6 36 %, PFS 13 weeks, OS 62 weeks
PFS6 0 %, PFS 1.5 months, OS 3.2 months*
DLTs proteinuria, diarrhea, hepatotoxicity; RR 17 %*
PFS6 and OS were 21.5 % and 12.1 months for AA and 16.7 % and 12.6 months for GB PFS 11.3 months, OS 13.9 months
MTD erlotinib 150 mg daily, sirolimus 5 mg daily
MTD 400 mg daily, PFS6 and OS were 6.5 % and 6.3 months in GBM and 7 % and 7.6 months in AG MTD sorafenib 800 mg daily and temsirolimus 25 mg weekly. PFS6 0 %, PFS 8 weeks* PFS6 and OS were 10.4 % and 9.4 months in the bev-naïve and 0 % and 4.4 months in the bev-resistant Median survival 10 months
RR 70 %, 6-mo nth PFS 70 %, PFS 8 months, OS 9.5 months
Stable disease 12 %, PFS 1 month, OS 6 months*
OS 5.7 months, 6-month PFS 14 %
RR 5 % , MTD not reached*
RR 0 %, PFS 8 weeks, OS 15 weeks*
6-month PFS 26 %, OS 7,4 months*
No. of Outcome patients
Recurrent/progressive GBM 18
Recurrent GBM
Recurrent GBM
Recurrent GBM
Phase Disease status
Pazopanib, Lapatinib
Temsirolimus, Bevacizumab
RAF/VEGFR/ PDGFR, mTOR VEGFR/PDGFR/ c-kit/FLT3 VEGF/bFGF
VEGFR/c-kit/ PDGFR, EGFR/ErbB EGFR, RAF/VEGFR/ Erlotinib, Sorafenib PDGFR VEGFR/FGFR/ PDGFR Nintedanib
Temsirolimus, bevacizumab Pazopanib, Lapatinib
Sorafenib, TMZ
Sorafenib
RAF/VEGFR/PDGFR
mTOR, VEGF
Regimen
Agents
Targets
Table 2 Published clinical trials for multiple-targets agents
Curr Oncol Rep (2014) 16:379 Page 7 of 14, 379
Imatinib, hydroxyurea
Imatinib
Imatinib
Imatinib
PDGFR/ c-kit/bcr-abl
PDGFR/ c-kit/bcr-abl
PDGFR/ c-kit/bcr-abl
Thalidomide
Imatinib
Thalidomide
Imatinib
Gefitinib, sirolimus
Imatinib
Thalidomide
Thalidomide
VEGF/bFGF
PDGFR/ c-kit/bcr-abl
VEGF/bFGF
PDGFR/ c-kit/bcr-abl
EGFR, mTOR
PDGFR/ c-kit/bcr-abl
VEGF/bFGF
VEGF/bFGF
Thalidomide
Thalidomide
Thalidomide , carmustine
Thalidomide, temozolomide, RT Thalidomide alone or with temozolomide Thalidomide
Imatinib, hydroxyurea
Gefitinib, sirolimus
Imatinib
Thalidomide, temozolomide
Thalidomide, cisplatin, temozolomide Imatinib, hydroxyurea
Lenalidomide
Lenalidomide, RT
Thalidomide, irinotecan
II
II
II
II
II
II
II
I
I/II
II
II
I
I
II
I
II
I
II
II
I
II
III
II
II
32
20
231
44
39
17
36
32
65
50
23
26
22
18
44
67
33
42 Recurrent high-grade glioma 39
Recurrent GBM
Recurrent high-grade glioma 40
Recurrent GBM
Newly diagnosed GBM
Newly diagnosed GBM
Recurrent GBM
Recurrent malignant glioma 34
Recurrent malignant glioma 50/55
Recurrent GBM
Recurrent AG
Malignant brain tumors
Recurrent brain tumors
Newly diagnosed malignant glioma Recurrent GBM
Newly diagnosed GBM
Newly diagnosed or recurrent GBM Newly diagnosed GBM
Recurrent GBM
[151]
[150]
[149]
[148]
Ref.
RR 6 %, 1-year OS 20.5 %
OS 31 weeks, 1-year OS 35 %
PFS 100 days, RR 24 %
OS and PFS 103 weeks and 36 weeks for thalidomide and temozolomide, and 63 weeks and 17 weeks for thalidomide. PFS 25 weeks, OS 36 weeks
PFS 22 weeks, OS 73 weeks
No DLTs with 1200 mg daily in non-EIAED patients. PFS6 3 % for GBM and 10 % in AG MTD: non- EIAED patients gefitinib 500 mg and sirolimus 5 mg daily, EIAED patients gefitinib 1000 mg and sirolimus 10 mg daily. DLTs: stomatitis, diarrhea, rash, thrombocytopenia. PFS6 27 %, PFS 14.4 weeks
RR 7 %, PFS6 24 %, PFS 15 weeks
PFS6 24 %, RR 10 %,
MTD 150 mg daily, DLTs thrombocytopenia and febrile neutropenia
MTD 20 mg/m2, PFS
