Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary brain tumor in humans. Over the past several decades, despite improvements in neurosurgical techniques, development of powerful chemotherapeutic agents, advances in radiotherapy, and comprehensive genomic profiling and molecular characterization, treatment of GBM has achieved very limited success in increasing overall survival. Thus, identifying and understanding the key molecules and barriers responsible for the malignant phenotypes and treatment resistance of GBM will yield new potential therapeutic targets. We review the most recent development of receptor tyrosine kinase targeted therapy for GBM and discuss the current status of several novel strategies with the emphasis on blood–brain barrier penetration as a major obstacle for small-molecule drugs to achieve their therapeutic goals. Likewise, a major opportunity for the treatment of GBM lies in the use of biomarkers for the discovery and development of new receptor tyrosine kinase targeted therapy.

Brain and other nervous system cancers rank 16th among the leading cancer types, with an estimated 23,890 new cases being diagnosed and an estimated 18,020 deaths in 2020 in the United States (1). Glioblastoma, also known as glioblastoma multiforme (GBM), is a grade 4 glioma and is the most common and lethal cancer of the central nervous system (CNS), with an incidence of about three cases per 100,000 adults per year, comprising about 15% of all primary brain tumors and 50% of the malignant types (2). GBM is pathologically diagnosed by the presence of high cellularity, high mitotic activity, with histologic hallmarks including pseudopalisading necrosis and/or microvascular proliferation (3). The median survival time for patients with GBM is only about a year upon diagnosis, and 5-year survival is less than 7%, even with maximum surgical removal of the malignancy followed by radiotherapy and chemotherapy (2). Its treatment resistance has been largely attributed to its notorious heterogeneity at the molecular and cellular level. In fact, it is well recognized that GBM is not a single disease but represents a collection of diseases with distinct cellular origin and molecular alterations.

GBM was one of the first types of cancer to be extensively profiled by the Cancer Genome Atlas project. These high-throughput analyses have cataloged a rich source of somatic mutations, copy-number alterations, transcriptional and epigenetic changes in GBM, and revealed biologically relevant alterations in three well-known molecular pathways in GBM: receptor tyrosine kinase (RTK) signaling, p53 signaling, and Rb-mediated G1 check point machinery (4, 5). A more detailed analysis of GBM, based on the whole-exome sequencing data of 291 patients, showed that at least one RTK was found altered in 67% of GBM overall. Specifically, the following alterations were found: EGFR (57%), platelet-derived growth factor receptor-alpha (PDGFRA) (13%), c-MET (1.6%), and FGFR (3.2%) (4). PI3K mutations were found in 25% of patients with GBM, and PTEN mutations or deletions were found in 41% of patients with GBM. Considering the RTK genes, PI3K genes, and PTEN, 89.6% of patients with GBM had at least one alteration in the PI3K pathway and 39% had two or more alterations. The neurofibromin 1 (NF1) gene was deleted or mutated in 10% of cases. The p53 pathway was found to be dysregulated in 86% of tumors, through mutation/deletion of TP53, amplification of mouse double minute (MDM) homolog 1/2/4, and/or deletion of cyclin-dependent kinase inhibitor 2A (CDKN2A). Concurrently, 79% of tumors had one or more alteration(s) affecting retinoblastoma (RB) gene function: 7.6% by direct RB1 mutation/deletion, 15.6% by amplification of cyclin-dependent kinases (CDKs) 4/6, and the remainder via CDKN2A deletion. Mutation of isocitrate dehydrogenase 1 (IDH1) has been found in about 5% of patients with GBM, showing high co-occurrence with TP53 and alpha-thalassemia/mental retardation syndrome X-linked (ATRX) mutations. Mutations in IDH1 and ATRX appear to be more prevalent in secondary GBM tumors (4).

The widespread differences in gene expression in GBM have led to the classification of GBM into proneural, neural, classical, and mesenchymal transcriptomic subtypes (6, 7). Verhaak and colleagues (8) recently removed the neural subgroup and reported subtype switching when comparing primary and recurrent GBM. It is noted that the pure computational analysis often reflects fluid GBM transcriptional cell states (9–11), and the biology of GBM tumorigenesis should be taken into account when discussing tumor subtype. The cell of origin has been shown to play an important role in determining GBM phenotype (12). More recently, Wang and colleagues (13) further proposed a cell lineage-based stratification model for GBM, highlighting how the cell of origin confers distinct molecular landscapes and therapeutic vulnerabilities.

Despite the continued improvement in surgical techniques and radiotherapy and chemotherapy procedures, the median survival time for patients with GBM has largely remained unchanged for over a decade. Standard of care for patients with GBM typically involves surgical removal of the tumor bulk, followed by radiation and alkylating chemotherapy with temozolomide (TMZ). A total dose of 60 Gy in 30 fractions is usually delivered for patients with GBM in 6 weeks, with five doses per week and concomitant daily TMZ, plus an additional six cycles of adjuvant TMZ treatment with 4 weeks between cycles (14). This protocol increased patient median survival from 12.1 months for the radiation-only group, to 14.8 months for patients who received both radiation plus TMZ; and 2-year survival from 10% for the radiation-only group, to 26% for patients who received both radiation and TMZ (15). The presence of O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation has been shown to be a predictor of responsiveness to alkylating chemotherapy and an independent favorable prognostic factor (16). MGMT is a DNA repair enzyme; it rescues tumor cells from DNA damage from alkylating agents, leading to resistance to chemotherapy. Epigenetic silencing of the MGMT gene by promoter methylation decreases MGMT protein expression, and leads to reduced DNA repair activity and increased sensitivity to therapy. However, not all GBM cases with MGMT promoter methylation will respond to alkylating chemotherapy, as it was reported that the MGMT locus was methylated in 48.5% of patients in a study cohort, and only the classical subtype of GBM showed positive correlation with MGMT DNA methylation status but the other subtypes did not (4).

In Table 1, we list known glioblastoma biological targets and associated therapeutic agents, both small molecules and antibodies, that have been reported in GBM clinical trials. We then elaborate on the expression and the characteristics of the important RTK primary targets in the discussions and list several preclinical small-molecule compounds that are under development for specific and prominent GBM RTK pathways in Table 2, where there exist opportunities for new agents to treat unmet medical needs. We also highlight new approaches and technologies for GBM treatment, namely, (i) tumor treating fields; (ii) immunotherapy; (ii) nanoparticles; (iv) oncolytic viruses; and conclude with (v) GBM RTK biomarkers and future opportunities.

Table 1.

Glioblastoma biological targets and associated therapeutic agents.

GBM biological targetsFull nameCategorySmall molecule or antibody
EGFR Epidermal growth factor receptor RTK Elortinib, gefitinib, afatinib, dacomitinib, osimertinib, AZD3759, epitinib, WSD0922, AEE788, nimotuzumab (mAb) 
PDGFRA Platelet derived growth factor receptor-alpha RTK Imatinib, sunitinib, cediranib, pazopanib, nintedanib, MEDI-575 (mAb) 
HER2/ERBB2 Human epidermal growth factor receptor 2 RTK Lapatinib, afatinib, dacomitinib, neratinib, tucatinib 
HER3/ERBB3 Human epidermal growth factor receptor 3 RTK TXI-85–1a, patritumab (mAb)a 
MET/HGFR Met proto-oncogene/hepatocyte growth factor receptor RTK Crizotinib, capmatinib, SGX523a, cabozantinib, INC280 
FGFR1/2/3 Fibroblast growth factor receptor RTK Pazopanib, nintedanib, dovitinib 
VEGFR1/2/3 Vascular endothelial growth factor receptor RTK Pazopanib, dovitinib, cabozantinib, AEE788, anlotinib, regorafenib, tivozanib, axitinib, PTK787, vandetanib 
KIT Kit proto-oncogene RTK Pazopanib, nintedanib, PLX3397 
IGF1R Insulin like growth factor 1 receptor RTK NVP-AEW541a 
CSF1R Colony-stimulating factor 1 receptor RTK PLX3397 
ALK Anaplastic lymphoma kinase RTK Crizotinib, ceritinib, lorlatinib, alectinib, repotrectinib 
ROS1 Ros proto-oncogene 1 RTK Crizotinib, entrectinib, lorlatinib, repotrectinib 
RET Ret proto-oncogene RTK Pralsetinib, selpercatinib, cabozantinib, vandetanib 
BTK Bruton tyrosine kinase RTK Ibrutinib, ACP-196 
EPHA3 Eph receptor A3 RTK KB004 (an anti-EphA3 antibody) 
NTRK1 Neurotrophic receptor tyrosine kinase 1 RTK Repotrectinib, AZD7451, repotrectinib 
AXL Axl receptor tyrosine kinase RTK Cabozantinib, BMS-777607, crizotinib, BGB324 
MER Mer proto-oncogene, tyrosine kinase RTK UNC569, UNC1062 
ABL Abelson murine leukemia viral oncogene homolog 1 nRTK Imatinib, nilotinib, dasatinib, bosutinib, bafetinib, ponatinib 
SRC1 Src proto-oncogene nRTK Dasatinib, bosutinib, KX2–391 
JAK1 Janus kinase 1 nRTK Ruxolitinib 
SMO Smoothened, frizzled class receptor GPCR Vismodegib, PF-04449913 
CXCR4 C-X-C motif chemokine receptor 4 GPCR AMD3100, plerixafor 
DRD2 Dopamine receptor D2 GPCR ONC201 
TGFBR1 Transforming growth factor beta-receptor 1 STK receptor Galunisertib 
TROP2/TACSTD2 Tumor associated calcium signal transducer 2 Cell surface glycoprotein Sacituzumab govitecan 
TIM3/HAVCR2 T-cell immunoglobulin mucin receptor 3 Cell surface immunoglobulin MBG453 (Ab) 
LAG3 Lymphocyte activating 3 Cell surface receptor BMS-986016 (mAb) 
ITGB1 (CD29) Integrin subunit beta-1 Cell surface receptor OS2966 (mAb) 
CD95 Fas cell surface death receptor Cell surface receptor CAN008, APG101 
ADAM10/17 Adam metallopepti-dase domain 10/17 Cell surface protease INCB7839 
AMPAR AMPA receptor Ligand-gated ion channel Talampanel 
ANGPT1/2 Angiopoietin 1/2 Secreted glycoprotein AMG 386 
PIGF Placental growth factor Growth factor RO5323441 (mAb) 
RAF Raf proto-oncogene STK Encorafenib, sorafenib, dabrafenib, vemurafenib 
MEK Mitogen-activated protein kinase kinase 1 Protein kinase Trametinib, binimetinib, PD-0325901, pimasertib 
ERK Mitogen-activated protein kinase 1 STK LY3214996 
p38 MAPK P38 MAP kinase/mitogen-activated protein kinase 14 STK Ralimetinib, LY2228820 
mTORC Mechanistic target of rapamycin kinase 1 STK Vistusertib, ABI-009, CC-115, GDC-0084, sirolimus 
CDK4/6 Cyclin dependent kinase 4/6 STK Abemaciclib, GLR2007, ribociclib 
Wee1 Wee1 G2 checkpoint kinase STK Adavosertib 
PRKCB Protein kinase C beta STK Enzastaurin 
DNA-PK DNA-dependent protein kinase STK CC-115 
PI3K phosphatidylinositol-4,5-bisphosphate 3-kinase Lipid kinase Paxalisib, buparlisib, PX 866, XL765, XL147, GDC-0084 
RAS Ras proto-oncogene, GTPase GTPase Tipifarnib 
IDH1/2 Isocitrate dehydrogenase 1/2 Isocitrate dehydrogenase FT-2102, IDH305, LY3410738 
IDO Indoleamine 2,3-dioxygenase 1/2 Heme enzyme Epacadostat, indoximod, BMS-986205 
FTASE Farnesyltransferase Farnesyltransferase Tipifarnib 
MDM2 Mouse double minute 2 Ring-type E3 ubiquitin transferase Idasanutlin 
PARP1 Poly(ADP-ribose) polymerase 1 Poly-ADP-ribosyltransferase Niraparib, pamiparib, olaparib, BSI-201, BGB290 
HMGCR 3-Hydroxy-3-methylglutaryl-CoA reductase Transmembrane enzyme Atorvastatin 
HDAC1 Histone deacetylase 1 Histone deacetylase Vorinostat 
TOPI/II DNA topoisomerase I/II DNA topoisomerase Edotecarin 
XPO1 Exportin 1 Nuclear transport receptor Selinexor 
STAT3 Signal transducer and activator of transcription 3 Transcription factor (TF) BBI608 
WT1 Wilms tumor 1 TF DSP-7888 
Proteasome Proteasome Proteasome Marizomib, ixazomib 
TUBULIN Beta-tubulin Microtubule MPC-6827, ortataxel, verubulin, patupilone 
GBM biological targetsFull nameCategorySmall molecule or antibody
EGFR Epidermal growth factor receptor RTK Elortinib, gefitinib, afatinib, dacomitinib, osimertinib, AZD3759, epitinib, WSD0922, AEE788, nimotuzumab (mAb) 
PDGFRA Platelet derived growth factor receptor-alpha RTK Imatinib, sunitinib, cediranib, pazopanib, nintedanib, MEDI-575 (mAb) 
HER2/ERBB2 Human epidermal growth factor receptor 2 RTK Lapatinib, afatinib, dacomitinib, neratinib, tucatinib 
HER3/ERBB3 Human epidermal growth factor receptor 3 RTK TXI-85–1a, patritumab (mAb)a 
MET/HGFR Met proto-oncogene/hepatocyte growth factor receptor RTK Crizotinib, capmatinib, SGX523a, cabozantinib, INC280 
FGFR1/2/3 Fibroblast growth factor receptor RTK Pazopanib, nintedanib, dovitinib 
VEGFR1/2/3 Vascular endothelial growth factor receptor RTK Pazopanib, dovitinib, cabozantinib, AEE788, anlotinib, regorafenib, tivozanib, axitinib, PTK787, vandetanib 
KIT Kit proto-oncogene RTK Pazopanib, nintedanib, PLX3397 
IGF1R Insulin like growth factor 1 receptor RTK NVP-AEW541a 
CSF1R Colony-stimulating factor 1 receptor RTK PLX3397 
ALK Anaplastic lymphoma kinase RTK Crizotinib, ceritinib, lorlatinib, alectinib, repotrectinib 
ROS1 Ros proto-oncogene 1 RTK Crizotinib, entrectinib, lorlatinib, repotrectinib 
RET Ret proto-oncogene RTK Pralsetinib, selpercatinib, cabozantinib, vandetanib 
BTK Bruton tyrosine kinase RTK Ibrutinib, ACP-196 
EPHA3 Eph receptor A3 RTK KB004 (an anti-EphA3 antibody) 
NTRK1 Neurotrophic receptor tyrosine kinase 1 RTK Repotrectinib, AZD7451, repotrectinib 
AXL Axl receptor tyrosine kinase RTK Cabozantinib, BMS-777607, crizotinib, BGB324 
MER Mer proto-oncogene, tyrosine kinase RTK UNC569, UNC1062 
ABL Abelson murine leukemia viral oncogene homolog 1 nRTK Imatinib, nilotinib, dasatinib, bosutinib, bafetinib, ponatinib 
SRC1 Src proto-oncogene nRTK Dasatinib, bosutinib, KX2–391 
JAK1 Janus kinase 1 nRTK Ruxolitinib 
SMO Smoothened, frizzled class receptor GPCR Vismodegib, PF-04449913 
CXCR4 C-X-C motif chemokine receptor 4 GPCR AMD3100, plerixafor 
DRD2 Dopamine receptor D2 GPCR ONC201 
TGFBR1 Transforming growth factor beta-receptor 1 STK receptor Galunisertib 
TROP2/TACSTD2 Tumor associated calcium signal transducer 2 Cell surface glycoprotein Sacituzumab govitecan 
TIM3/HAVCR2 T-cell immunoglobulin mucin receptor 3 Cell surface immunoglobulin MBG453 (Ab) 
LAG3 Lymphocyte activating 3 Cell surface receptor BMS-986016 (mAb) 
ITGB1 (CD29) Integrin subunit beta-1 Cell surface receptor OS2966 (mAb) 
CD95 Fas cell surface death receptor Cell surface receptor CAN008, APG101 
ADAM10/17 Adam metallopepti-dase domain 10/17 Cell surface protease INCB7839 
AMPAR AMPA receptor Ligand-gated ion channel Talampanel 
ANGPT1/2 Angiopoietin 1/2 Secreted glycoprotein AMG 386 
PIGF Placental growth factor Growth factor RO5323441 (mAb) 
RAF Raf proto-oncogene STK Encorafenib, sorafenib, dabrafenib, vemurafenib 
MEK Mitogen-activated protein kinase kinase 1 Protein kinase Trametinib, binimetinib, PD-0325901, pimasertib 
ERK Mitogen-activated protein kinase 1 STK LY3214996 
p38 MAPK P38 MAP kinase/mitogen-activated protein kinase 14 STK Ralimetinib, LY2228820 
mTORC Mechanistic target of rapamycin kinase 1 STK Vistusertib, ABI-009, CC-115, GDC-0084, sirolimus 
CDK4/6 Cyclin dependent kinase 4/6 STK Abemaciclib, GLR2007, ribociclib 
Wee1 Wee1 G2 checkpoint kinase STK Adavosertib 
PRKCB Protein kinase C beta STK Enzastaurin 
DNA-PK DNA-dependent protein kinase STK CC-115 
PI3K phosphatidylinositol-4,5-bisphosphate 3-kinase Lipid kinase Paxalisib, buparlisib, PX 866, XL765, XL147, GDC-0084 
RAS Ras proto-oncogene, GTPase GTPase Tipifarnib 
IDH1/2 Isocitrate dehydrogenase 1/2 Isocitrate dehydrogenase FT-2102, IDH305, LY3410738 
IDO Indoleamine 2,3-dioxygenase 1/2 Heme enzyme Epacadostat, indoximod, BMS-986205 
FTASE Farnesyltransferase Farnesyltransferase Tipifarnib 
MDM2 Mouse double minute 2 Ring-type E3 ubiquitin transferase Idasanutlin 
PARP1 Poly(ADP-ribose) polymerase 1 Poly-ADP-ribosyltransferase Niraparib, pamiparib, olaparib, BSI-201, BGB290 
HMGCR 3-Hydroxy-3-methylglutaryl-CoA reductase Transmembrane enzyme Atorvastatin 
HDAC1 Histone deacetylase 1 Histone deacetylase Vorinostat 
TOPI/II DNA topoisomerase I/II DNA topoisomerase Edotecarin 
XPO1 Exportin 1 Nuclear transport receptor Selinexor 
STAT3 Signal transducer and activator of transcription 3 Transcription factor (TF) BBI608 
WT1 Wilms tumor 1 TF DSP-7888 
Proteasome Proteasome Proteasome Marizomib, ixazomib 
TUBULIN Beta-tubulin Microtubule MPC-6827, ortataxel, verubulin, patupilone 

Abbreviations: GPCR, G protein-coupled receptor; nRTK, non-receptor tyrosine kinase; RTK, receptor tyrosine kinase; STK, serine/threonine kinase.

aNot yet into GBM clinical trial.

Table 2.

Small-molecule inhibitors targeting prominent GBM RTK pathways.

Small-molecule inhibitors targeting prominent GBM RTK pathways.
Small-molecule inhibitors targeting prominent GBM RTK pathways.

RTK targeted therapy

There are at least three major areas awaiting breakthroughs that would lead to better GBM management: (i) a better understanding of the heterogenous nature of the disease to provide more drug targets and rational patient stratification; (ii) overcoming the blood–brain barrier (BBB) to achieve better drug delivery and efficacy; and (iii) elucidating the mechanisms of treatment resistance to help design combinatory strategies. With the discovery of key signaling pathways involved in GBM tumorigenesis, targeted agents hold great promise as monotherapy or as sensitizing strategies to improve response to traditional radio-chemotherapy. These agents include inhibitors of RTK signaling, cell cycle and DNA damage repair pathways, and angiogenesis. However, despite intense research endeavors and numerous clinical trials, no targeted agent for GBM has been approved by the FDA in the past decade.

EGFR, HER2, PDGFRA, c-MET, FGFR, and VEGFR have all emerged as highly attractive therapeutic targets in GBM based on the identification of their amplification or mutation in GBM as an upstream trigger of dysregulated cell signaling cascades (Fig. 1). Although there have been many tyrosine kinase inhibitors (TKIs) approved for the treatment of cancers that reside outside of the CNS, no kinase inhibitor has been approved for the treatment of primary CNS tumors. The main reason for these failures is the poor blood-brain barrier (BBB) penetration of these kinase inhibitors. In fact, a majority of TKIs are substrates of efflux transporters such as P-glycoprotein (P-GP) and breast cancer resistance protein (BCRP), and do not attain significant free brain penetration. The challenge of designing TKIs with suitable BBB penetration is an opportunity for future TKI development (17). We will summarize in the following section the current status of small-molecule inhibitors that target the prominent RTK signaling in GBM (Fig. 1; Table 2).

Figure 1.

Prominent RTKs found altered in GBM and representative small-molecule kinase inhibitors that target these RTK signaling pathways. Numbers in the parentheses are established gene alteration rates for each marked RTK. T, tumor; V, vessel.

Figure 1.

Prominent RTKs found altered in GBM and representative small-molecule kinase inhibitors that target these RTK signaling pathways. Numbers in the parentheses are established gene alteration rates for each marked RTK. T, tumor; V, vessel.

Close modal

EGFR TKIs

Approximately 57% of GBM patient samples contain various EGFR mutations, often with focal amplification, and about half of these have an associated extracellular mutation of EGFRvIII, which has extracellular domain truncation from exons 2 to 7 and is constitutively active (4). Several EGFR inhibitors, including gefitinib, erlotinib, lapatinib, dacomitinib, and osimertinib, have been approved for use in EGFR mutated non–small cell lung cancer (NSCLC) and/or HER2 positive breast cancer; however, clinical trial data in GBM collectively suggest that these EGFR inhibitors are not of value for patients with GBM (18), showing no survival improvement compared with standard-of-care chemoradiation in patients with newly diagnosed GBM (19), or in patients with recurrent disease (20). Many factors may contribute to these disappointing results. Among these, a pharmacokinetic (PK) failure due to the poor BBB penetration for these inhibitors likely accounts for the most, because effective target inhibition has never been demonstrated. More recent development of EGFR inhibitors includes dacomitinib, osimertinib, AZD3759, epitinib, and WSD0922. Among them, AZD3759 has been demonstrated to have effective penetration across the BBB in both rat and monkey (17, 21). Presently, AZD3759 is under clinical trial for NSCLC with brain metastasis. Epitinib was reported as a selective EGFR TKI designed for optimal brain penetration (22). Epitinib was well tolerated in patients, and clear clinical efficacy was observed in patients with untreated EGFR-mutant NSCLC with brain metastases (BMs) (22). A clinical trial for epitinib in treating patients with GBM is ongoing (NCT03231501). Zhong and colleagues (23) reported WSD0922 as a novel selective EGFR inhibitor with potent activity, excellent CNS penetration, a good safety profile, and preclinical antitumor efficacy in a GBM PDX model. AZD3759, epitinib, and WSD0922 together hold promise to assess the role of EGFR signaling inhibition in GBM treatment.

HER2 TKIs

The role of HER2/ERBB2 in primary GBM is becoming better understood in a subgroup of GBM tumors marked by ERBB3-SOX10High-EGFR-SOX9Low expression, identified in a cell of origin-based strategy in GBM mouse models and PDX in a recent study (13). Agents that attenuate HER2 function have been investigated in patients with HER2-positive breast cancer. Among patients treated with trastuzamab, a monoclonal HER2 antibody that binds to an extracellular domain of HER2, BM emerge in approximately 30% of patients (24). As a dual EGFR/HER2 inhibitor, lapatinib has been approved as a small-molecule inhibitor for HER2-positive breast cancer (25), but preclinical studies showed that therapeutic effects were not achieved in BM, suggesting that lapatinib does not efficiently cross the BBB (18). The tolerability and safety for lapatinib have been trialed in patients with GBM and its efficacy remains to be determined (18, 26). Neratinib is a pan-EGFR inhibitor that binds covalently with cysteine residues Cys-773 and Cys-805 in EGFR and HER2, respectively, in the ATP binding pocket (27). Neratinib was reported as a substrate of P-gp and Bcrp, and has limited brain penetration in mice (17). Accordingly, a phase II trial of neratinib in patients with HER2-positive brain metastases was not successful (28). Neratinib has been trialed in INSIGhT (NCT02977780), a biomarker-based, Bayesian adaptively randomized, multi-arm phase II platform screening trial for patients with newly diagnosed GBM and unmethylated MGMT promoters (29). Tucatinib was reported to be able to cross the BBB and was capable of inhibiting phospho-HER2 in mouse brain tissue, demonstrating a certain extent of free penetration (30). In addition, tucatinib achieved a survival benefit in mice in an intracranial HER2-positive xenograft study (31). A phase Ib clinical study of tucatinib in HER2-positive breast cancer found substantial benefit for patients with isolated BM progression (32). Even more interesting, in patients with HER2-positive breast cancer with BM, the addition of tucatinib to trastuzumab and capecitabine treated patients was reported to produce better progression-free survival and overall survival (33, 34). As of today, 26 clinical trials for tucatinib are completed or still ongoing. Well-designed preclinical and clinical trials are warranted to determine the effectiveness of tucatinib as a potential drug for GBM treatment.

PDGFR TKIs

Approximately 13% of patients with GBM carry an altered PDGFRA gene. At least 14 inhibitors of PDGFR have been evaluated for their potential in the treatment of CNS tumors. Unfortunately, few were expected to freely penetrate the BBB (17). Single-agent imatinib was shown to have minimal activity in recurrent malignant gliomas in a phase I/II trial (35). Cediranib and pazopanib have been studied in phase II trials in patients with GBM but did not show a survival benefit (36, 37). Likewise, because of their poor BBB penetration, sunitinib, sorafenib, nintedanib, tivozanib, and dovitinib were ineffective in clinical GBM studies (17). Crenolanib, an orally bioavailable benzamidazole that selectively and potently inhibits signaling of wild-type and mutant isoforms of the PDGFR family, was shown to effectively block PDGFRα phosphorylation and downstream AKT signaling in Ink4a/Arf−/− mouse astrocytes transfected to stably co-express both human PDGFRα and PDGF AA (38), and has been studied in a phase II clinical trial in patients with GBM with PDGFRA gene amplification (NCT02626364). Effective PDGFRA inhibitors represent a significant unmet need in light of the prominent presence of dysregulated PDGFR signaling in a subset of patients with GBM.

C-MET TKIs

Mutation of c-MET was found in only about 1.6% of GBM cases; however, the MET pathway is prominently activated in GBM cells (39). As revealed by an Affymetrix U133 array study, increased c-MET expression represents a significant portion of GBM cases that do not have high expression of EGFR and ERBB3, suggesting a potential new GBM subtype that is distinct from what has been proposed for cases with high EGFR or ERBB3 expression (Fig. 2; also see later discussion). Therefore, targeting c-MET could lead to selective killing of tumor cells with dysregulated MET signaling. Of the existent c-MET inhibitors, for example, foretinib and SGX523, there are no data to support their brain penetration or whether they are substrates of efflux transporters (17). Encouraging results were reported for cabozantinib, which inhibits both c-MET and VEGFR2, in a phase II study for patients with relapsed GBM. However, significant side effects were also reported (40). Capmatinib (INC280), an oral, highly potent and selective MET inhibitor, has been recently granted breakthrough therapy designation as a first-line treatment for patients with metastatic MET exon14 skipping-mutated NSCLC, and is under active GBM clinical evaluation (NCT02386826).

Figure 2.

cBioportal TCGA GBM samples with U133 microarray data (A), and RNA-seq data (B) were queried for EGFR, ERBB3, and MET gene expression and revealed that high expression of EGFR, ERBB3, and MET are represented in distinct subpopulations.

Figure 2.

cBioportal TCGA GBM samples with U133 microarray data (A), and RNA-seq data (B) were queried for EGFR, ERBB3, and MET gene expression and revealed that high expression of EGFR, ERBB3, and MET are represented in distinct subpopulations.

Close modal

VEGFR inhibitors

VEGFR is overactivated in the majority of patients with GBM via the overexpression of VEGF (41). Overexpression of VEGF correlates with tumor vessel density and poor patient prognosis (40, 41). VEGFR is frequently inhibited by PDGFR inhibitors, such as cediranib, pazopanib, and other inhibitors mentioned earlier for PDGFR, but few were expected to penetrate the BBB (17), thus limiting their effectiveness in GBM treatment. Cabozantinib, a small-molecule inhibitor of VEGFR2 and c-Met that is used in treating patients with medullary thyroid cancer and renal cell carcinoma, has been evaluated in a phase II GBM trial (NCT00704288), with clinical activity reported in patients with recurrent GBM naive to antiangiogenic therapy, although the predefined statistical target for success was not met (42). Therapeutic strategies to inhibit signaling via VEGFR2 and activation of the VEGF pathway also include mAbs directed against VEGF or VEGFR. Bevacizumab, a humanized mAb against VEGF that has been evaluated in clinical trials for the treatment of GBM, revealed no benefit (43). In a retrospective study, clinical benefits of bevacizumab were suggested for newly diagnosed proneural GBM, although these benefits remain to be validated (44).

TKIs with significant free brain penetration for PI3K (GDC-0084, buparlisib) have been reported and have entered clinical trials (17, 45, 46), but their clinical benefits remain to be determined. In addition to small molecules targeting angiogenesis and intrinsic RTK signaling, other therapies have been extensively explored in treating GBM.

Tumor treating fields

Tumor treating fields (TTFs) is a noninvasive, wearable technology based on low-intensity alternating electric fields that disrupt mitosis and inhibit tumor growth (47). A portable device, NovoTTF-100A, was evaluated in a phase III trial of chemotherapy-free treatment versus active chemotherapy in the treatment of patients with recurrent GBM and showed no improvement in overall survival (48). The efficacy and activity with this device appears comparable to chemotherapy regimens that are commonly used for recurrent GBM, but toxicity and quality of life clearly favor TTFs (48). The results from this trial lead to the 2011 FDA approval of NovoTTF-100A for treatment of patients with recurrent GBM. Stupp and colleagues (49) reported the final results of a randomized, open-label trial, with 695 patients with GBM with resected or biopsied tumors who had completed concomitant radiochemotherapy. The addition of TTFs to maintenance TMZ chemotherapy versus maintenance TMZ alone, resulted in statistically significant improvement in progression-free survival and overall survival (49). The TTF device was subsequently approved as an adjuvant therapy for newly diagnosed patients with GBM in 2015. The combination of TTFs with other therapies, such as radiation therapy, chemotherapy, and immunotherapy, are areas of active pursuit, with more than 20 ongoing clinical trials.

Immunotherapy

Programmed cell death protein 1/programmed death ligand-1

The programmed cell death protein 1 (PD-1)/programmed death ligand-1 (PD-L1) pathway plays an important role in suppressing the function of T cells in eradicating tumor cells (50). PD-L1 is upregulated in several types of solid tumors, and high expression levels of PD-L1 often indicate better clinical efficacy of PD-1/PD-L1 checkpoint blockades (50, 51). PD-1/PD-L1 checkpoint blockades have achieved significant progress in several cancers. Pembrolizumab, which targets PD-1, has been approved as a first-line treatment for NSCLC (52), melanoma (53), and other metastatic solid tumors (54). However, PD-1/PD-L1 inhibition in GBM has not achieved breakthroughs, because of the low immunogenic response and immunosuppressive microenvironment of GBM (55). A phase III clinical trial reported that nivolumab, which targets PD-1, did not demonstrate survival benefits compared with bevacizumab in recurrent patients with GBM (56). There are many ongoing clinical trials exploring the efficacy of various strategies based on PD-1/PD-L1 checkpoint blockade in primary or recurrent patients with GBM. Many challenges for application of immune checkpoint blockade in GBM exist, including BBB penetration for anti–PD-1 or PD-L1 agents, better stratification of patients for their best response, and the identification of the optimal combination strategy.

Chimeric Antigen Receptor T Cells

Seventeen chimeric antigen receptor (CAR) T-cell trials for GBM have been registered, targeting surface antigens including EGFRvIII, B7-H3, CD147, L13Ra2, and memory enriched T cells expressing CD19CAR-CD28-CD3zeta-EGFRt. The results for the feasibility and safety of CAR T-cell therapy are promising (57), yet its efficacy as a monotherapy or in combination, and the challenges of optimizing cell manufacture and cell infusion processes, local proliferation, and how to overcome the immunosuppressive environment of GBM remain to be studied.

Indoleamine 2,3-dioxygenase inhibitors

Indoleamine 2,3-dioxygenase (IDO) 1 and 2 and tryptophan 2,3-dioxigenase (TDO2) are the first and rate-limiting catabolic enzymes in the degradation pathway of the essential amino acid tryptophan. IDO was postulated to limit innate and adaptive immune responses by depleting immune effector cells of Trp and by promoting the accumulation of Kyn and some of its derivatives (58). IDO has since emerged as a key target in cancer immunotherapy. High tumor expression of IDO is an independent risk factor for poor outcome in a variety of human cancers, including GBM (59). Over the years, various IDO inhibitors like 1-methyltryptophan, indoximod, epacadostat, navoximod, BMS-986205, PF-06840003, and BGS-5777 have been developed (60). Among them, indoximod, epacadostat, and BMS-986205 are under active clinical evaluation for patients with GBM in a combinatory setting with anti–PD-1 and chemo- and/or radio-therapies (NCT02502708, NCT02052648, NCT03707457, NCT04047706). BGB-5777, a potent CNS-penetrating IDO1 inhibitor, has been shown to confer a durable survival benefit in orthotopic GBM mouse models when combined with anti–PD-1 and radiation therapy (61).

Nanoparticles

Nanoparticles are small structures made by either inorganic, polymeric, or organic materials with a size of a nanometer scale, which can be implanted with active agents. These agents include immune cells, chemotherapeutic drugs, or sensitizers, that can target GBM cellular receptors or angiogenic blood vessels, or open the BBB to help the active agents to reach GBM cells (62).

Extracellular vesicles (EVs), including exosomes and microvesicles, are submicron lipid bilayer-surrounded vesicles containing proteins and nucleic acids, such as miRNAs and mRNAs. Exosomes are the smallest biological vesicles (30–100 nm) and are derived from the endosomal system (63). They are released from many, if not all, cell types in the body and are believed to play a role in intercellular communication. The ability of EVs to selectively convey proteins, lipids, and nucleic acids to cells has created excitement in the field of drug delivery, as exemplified by GPI-anchored anti-EGFR nanobodies (64). In GBM, the tumor-specific EGFRvIII was detected in serum microvesicles from patients but not from healthy controls (65). Harshyne and colleagues (66) reported that GBM cell lines secrete exosomes with high immunogenic ability. And miRNAs were found highly enriched in EVs derived from cerebrospinal fluid (CSF) of patients with GBM (67, 68), suggesting a potential use of CSF and serum exosomes as a diagnostic biomarker platform. The use of exosomes as a therapeutic vehicle for GBM is burgeoning, as exemplified by a report that low miR-151a levels of patients with GBM correlated with a poor response to TMZ therapy, and this TMZ resistance phenotype can be overcome by overexpression of miR-151a and passed in an exosome-dependent manner to confer sensitivity in resistance cells (69). As a delivery vehicle, nanoparticles are thought to have sustained therapeutic releases and low safety concerns; however, the challenge remains to achieve BBB penetration and tumor-specific targeting. Intracranial tumor cavity post-surgery injection is practical to bypass the need for BBB penetration, but it is challenging to control drug release at an effective and enduring concentration. In addition, the limited intratumoral distribution is another concern (62).

Oncolytic viruses

Oncolytic viruses are a distinct class of antitumor agents with a unique mechanism of action that kills tumor cells directly through oncolytic replication and then proceeds to infect tumor cells in proximity, while sparing normal tissues and generating beneficial outcomes in patients (70). As a versatile vehicle for expressing immunomodulatory transgenes or cell killing moieties, oncolytic viruses have been heavily investigated. Patel and colleagues (71) reported an oncolytic herpes simplex virus (oHSV) that expresses antitumor cytokine IL12. Two studies have used apoptosis inducing genes such as TRAIL in oncolytic adenovirus vectors (Ad5/Ad35.IR-E1A/TRAIL) and (CRAd5/11-D24.TRAIL/arresten), and showed promising results with increased antiangiogenesis and enhanced tumor apoptosis activity (72, 73). IL24/MDA-7, a member of the IL10 gene family with a broad range of antitumor properties, when expressed via a recombinant replication-defective adenovirus, Ad.mda-7, was reported to have profound antiproliferative and cytotoxic effects in GBM cells both in vitro and in vivo (74). Kim and colleagues (75) reported a granulocyte macrophage colony-stimulating factor (GM-CSF)–expressing vaccinia virus (VV) JX-594. The potential role of immune checkpoint inhibitor anti–PD-1 antibody has also been investigated in an oHSV system (scFvPD-1)(76). Oncolytic viruses have demonstrated promising antitumor effects in vitro and in vivo in preclinical models. Stereotactic injections or resection bed inoculation are the most commonly used methods for introducing viral vectors into high grade gliomas. Mesenchymal stem cells (MSCs) and neural stem cells (NSCs) carrying oncolytic adenoviruses have also been reported to yield improved results compared with the viral injection alone (77, 78). More recently, Frederick and colleagues (79) reported a phase Ib randomized study of DNX-2401, with a replication-competent, tumor-selective, oncolytic adenovirus with enhanced infectivity in recurrent patients with GBM. This study revealed good tolerance and encouraging results that warrant further investigation. Currently, there are more than 14 ongoing GBM clinical trials that are exploring the oncolytic virus vector as monotherapy or in combination with other therapies.

The genetic and epigenetic advancements in GBM have allowed the identification of prominent molecular biomarkers such as MGMT, IDH, EGFR, and several others that are expressed differently in different molecular subtypes of GBM, and have led to the development of biomarker-based therapeutics (80). Biomarkers have proven to be of high value and could eventually be utilized as drug targets, and this has been well exemplified in EGFR-mutant NSCLC where multiple generations of EGFR inhibitors have been developed. In 2015, accelerated approval of osimertinib was granted for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC, as detected by an FDA-approved test, who have progressed on or after EGFR TKI therapy (81). It has been shown that drugs developed using a biomarker-based strategy were associated with a significantly shorter clinical phase of development and a numerically shorter time to approval (82).

A recent cell-of-origin–based GBM stratification study has identified two types of GBM that are characterized by high EGFR and high ERBB3 expression, respectively (13). The scheme covers about 43% of total GBM cases, with more than half of the GBM cases to be assigned as yet determined additional subtypes. Alternative RTK signaling has been often reported as a mechanism of GBM resistance; for example, c-MET expression was shown to confer resistance to EGFR inhibition (83); and activation of c-MET and ERBB3 leads to tolerance of lung cancer cells to gefitinib, an inhibitor targeting EGFR (84). To investigate the potential of c-MET as a biomarker for a subset of GBM cases, we queried the expression of c-MET in TCGA 528 GBM cases with U133 microarray results. This query shows that a significant portion of the cases without high EGFR or high ERBB3 expression are indeed marked by high MET expression, and these high MET expression cases are mutually exclusive from cases with high EGFR expression (Fig. 2A). The existence of a subset of GBM cases with high MET expression was further confirmed by a query based on RNA sequencing data from a different data set (Fig. 2B). Identification of the cell of origin and characterization of tumor phenotypes of this putative new GBM subset would further expand the territory of the categorized GBM landscape and assist the development of GBM targeted therapy. Such advancement would lead to the identification of a novel cell lineage-based GBM signature that is distinct from what has been established in type I and type II GBMs by Wang and colleagues (13). This advancement would also help in compiling panels of more comprehensive biomarkers for a better lineage based patient stratification. In addition to having signaling dependence that is dominant in a given tumor subgroup with certain RTK(s), complex phenotypes in GBM are rooted in the coexistence of multiple signaling routes that require drug combinations targeting each of the representative signaling components. Looking forward, a better understanding of mechanisms that lead to synergistic effects of drug combinations and strategies to identify drug synergy is highly desirable for GBM treatment. Although this mechanistic work is challenging, great progress has been made in this direction (85–87).

The identification of GBM subtypes that are supported by distinct RTK signaling would underscore the need for development of a battery of inhibitors that target different RTKs to be applied to different patients accordingly or in combination. Relevant RTKs in GBM, including EGFR, FGFR, PDGFRA, ERBB2, ERBB3, c-MET, VEGFR, and TGFRB, drive the dysfunction of downstream signaling such as PI3K/AKT/mTOR, P53, and RB1 pathways, and open up possible therapies for GBM by targeting these pathways with selective inhibitors (4). Thus far, there are very few reports of the design of kinase inhibitors specifically for the treatment of brain tumors, and only a few kinase inhibitors were reported to achieve brain penetration, with three for EGFR (AZD379, epitinib, WSD0922), one for ERBB2 (tucatinib), one for c-MET (cabozantinib), two for PI3K (GDC0084, buparlisib), two for MEK (PD0325901, pimasertib), but none for FGFR, PDGFR, VEGFR, or TGFRB (17). It is, thus imperative to increase the arsenal of inhibitors that can penetrate the BBB to expand and improve the treatment of brain cancer. Using high throughput platforms, it is plausible to screen and identify inhibitory small molecules that specifically target each individual RTK arm of influence under culture conditions supplied with ligand-specific culture medium. For each potential RTK target, opportunities lie ahead for additional or improved treatments that are specifically designed for GBM.

No disclosures were reported.

1.
Howlader
N
,
Noone
AM
,
Krapcho
M
,
Miller
D
,
Brest
A
,
Yu
M
, et al
SEER Cancer Statistics Review, 1975–2017
,
Bethesda, MD
:
National Cancer Institute
. 
2020
, https://seer.cancer.gov/csr/1975_2017/,
based on November 2019 SEER data submission, posted to the SEER web site
.
2.
Ostrom
QT
,
Gittleman
H
,
Truitt
G
,
Boscia
A
,
Kruchko
C
,
Barnholtz-Sloan
JS
. 
CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2011–2015
.
Neuro Oncol
2018
;
20
:
iv1
iv86
.
3.
Louis
DN
,
Perry
A
,
Reifenberger
G
,
von Deimling
A
,
Figarella-Branger
D
,
Cavenee
WK
, et al
The 2016 World Health Organization classification of tumors of the central nervous system: A summary
.
Acta Neuropathol
2016
;
131
:
803
20
.
4.
Brennan
CW
,
Verhaak
RGW
,
McKenna
A
,
Campos
B
,
Noushmehr
H
,
Salama
SR
, et al
The somatic genomic landscape of glioblastoma
.
Cell
2013
;
155
:
462
77
.
5.
N. Cancer Genome Atlas Research
. 
Comprehensive genomic characterization defines human glioblastoma genes and core pathways
.
Nature
2008
;
455
:
1061
8
.
6.
Phillips
HS
,
Kharbanda
S
,
Chen
R
,
Forrest
WF
,
Soriano
RH
,
Wu
TD
, et al
Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis
.
Cancer Cell
2006
;
9
:
157
73
.
7.
Verhaak
RGW
,
Hoadley
KA
,
Purdom
E
,
Wang
V
,
Qi
Y
,
Wilkerson
MD
, et al
Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1
.
Cancer Cell
2010
;
17
:
98
110
.
8.
Wang
Q
,
Hu
B
,
Hu
X
,
Kim
H
,
Squatrito
M
,
Scarpace
L
, et al
Tumor evolution of glioma-intrinsic gene expression subtypes associates with immunological changes in the microenvironment
.
Cancer Cell
2017
;
32
:
42
56
e46.
9.
Sottoriva
A
,
Spiteri
I
,
Piccirillo
SGM
,
Touloumis
A
,
Collins
VP
,
Marioni
JC
, et al
Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics
.
Proc Natl Acad Sci U S A
2013
;
110
:
4009
14
.
10.
Patel
AP
,
Tirosh
I
,
Trombetta
JJ
,
Shalek
AK
,
Gillespie
SM
,
Wakimoto
H
, et al
Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma
.
Science
2014
;
344
:
1396
401
.
11.
Neftel
C
,
Laffy
J
,
Filbin
MG
,
Hara
T
,
Shore
ME
,
Rahme
GJ
, et al
An integrative model of cellular states, plasticity, and genetics for glioblastoma
.
Cell
2019
;
178
:
835
49
.
12.
Alcantara Llaguno
SR
,
Wang
Z
,
Sun
D
,
Chen
J
,
Xu
J
,
Kim
E
, et al
Adult lineage-restricted CNS progenitors specify distinct glioblastoma subtypes
.
Cancer Cell
2015
;
28
:
429
40
.
13.
Wang
Z
,
Sun
D
,
Chen
Y-J
,
Xie
X
,
Shi
Y
,
Tabar
V
, et al
Cell lineage-based stratification for glioblastoma
.
Cancer Cell
2020
;
38
:
366
79
.
14.
Stupp
R
,
Hottinger
AF
,
van den Bent
MJ
,
Dietrich
PY
,
Brandes
AA
. 
Frequently asked questions in the medical management of high-grade glioma: a short guide with practical answers
.
Ann Oncol
2008
;
19
:
vii209
216
.
15.
Stupp
R
,
Mason
WP
,
van den Bent
MJ
,
Weller
M
,
Fisher
B
,
Taphoorn
MJB
, et al
Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma
.
N Engl J Med
2005
;
352
:
987
96
.
16.
Hegi
ME
,
Diserens
A-C
,
Gorlia
T
,
Hamou
M-F
,
de Tribolet
N
,
Weller
M
, et al
MGMT gene silencing and benefit from temozolomide in glioblastoma
.
N Engl J Med
2005
;
352
:
997
1003
.
17.
Heffron
TP
. 
Small molecule kinase inhibitors for the treatment of brain cancer
.
J Med Chem
2016
;
59
:
10030
66
.
18.
Reardon
DA
,
Wen
PY
,
Mellinghoff
IK
. 
Targeted molecular therapies against epidermal growth factor receptor: past experiences and challenges
.
Neuro Oncol
2014
;
16
:
viii7
13
.
19.
Uhm
JH
,
Ballman
KV
,
Wu
W
,
Giannini
C
,
Krauss
JC
,
Buckner
JC
, et al
Phase II evaluation of gefitinib in patients with newly diagnosed Grade 4 astrocytoma: Mayo/North Central Cancer Treatment Group Study N0074
.
Int J Radiat Oncol Biol Phys
2011
;
80
:
347
53
.
20.
Raizer
JJ
,
Abrey
LE
,
Lassman
AB
,
Chang
SM
,
Lamborn
KR
,
Kuhn
JG
, et al
A phase II trial of erlotinib in patients with recurrent malignant gliomas and nonprogressive glioblastoma multiforme postradiation therapy
.
Neuro Oncol
2010
;
12
:
95
103
.
21.
Zeng
Q
,
Wang
J
,
Cheng
Z
,
Chen
K
,
Johnström
P
,
Varnäs
K
, et al
Discovery and evaluation of clinical candidate AZD3759, a potent, oral active, central nervous system-penetrant, epidermal growth factor receptor tyrosine kinase inhibitor
.
J Med Chem
2015
;
58
:
8200
15
.
22.
Qing Zhou
BG
,
Yuan
L
,
Hua
Y
,
Wu
Y-L
. 
The safety profile of a selective EGFR TKI epitinib (HMPL-813) in patients with advanced solid tumors and preliminary clinical efficacy in EGFRm+ NSCLC patients with brain metastasis
.
J Clin Oncol
34
:
15s
, 
2016
(
suppl. abstr. e20502
).
23.
Wei Zhong
JZ
,
Mu
A
,
Sun
C
. 
WSD0922: a BBB penetrable EGFR/EGFRVIII inhibitor for the treatment of GBM and metastatic CNS tumor
.
Cancer Res
79
:
13s
, 
2019
(
suppl. abstr. 1326
).
24.
Brufsky
AM
,
Mayer
M
,
Rugo
HS
,
Kaufman
PA
,
Tan-Chiu
E
,
Tripathy
D
, et al
Central nervous system metastases in patients with HER2-positive metastatic breast cancer: incidence, treatment, and survival in patients from registHER
.
Clin Cancer Res
2011
;
17
:
4834
43
.
25.
Higa
GM
,
Abraham
J
. 
Lapatinib in the treatment of breast cancer
.
Expert Rev Anticancer Ther
2007
;
7
:
1183
92
.
26.
Yu
A
,
Faiq
N
,
Green
S
,
Lai
A
,
Green
R
,
Hu
J
, et al
Report of safety of pulse dosing of lapatinib with temozolomide and radiation therapy for newly-diagnosed glioblastoma in a pilot phase II study
.
J Neurooncol
2017
;
134
:
357
62
.
27.
Feldinger
K
,
Kong
A
. 
Profile of neratinib and its potential in the treatment of breast cancer
.
Breast Cancer
2015
;
7
:
147
62
.
28.
Freedman
RA
,
Gelman
RS
,
Wefel
JS
,
Melisko
ME
,
Hess
KR
,
Connolly
RM
, et al
Translational breast cancer research consortium (TBCRC) 022: A phase II trial of neratinib for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases
.
J Clin Oncol
2016
;
34
:
945
52
.
29.
Alexander
BM
,
Trippa
L
,
Gaffey
S
,
Arrillaga-Romany
IC
,
Lee
EQ
,
Rinne
ML
, et al
Individualized screening trial of innovative glioblastoma therapy (INSIGhT): a bayesian adaptive platform trial to develop precision medicines for patients with glioblastoma
.
JCO Precis Oncol
2019
;
3
:
PO.18.00071
.
30.
Dinkel
V
,
Anderson
D
,
Winski
S
;
Winkler
J
;
Koch
K
;
Lee
PA
. 
Abstract 852: ARRY-380, a potent, small molecule inhibitor of ErbB2, increases survival in intracranial ErbB2+ xenograft models in mice
.
Cancer Res
2012
;
72
:
852
.
31.
Kulukian
A
,
Lee
P
,
Taylor
J
,
Rosler
R
,
de Vries
P
,
Watson
D
, et al
Preclinical activity of HER2-selective tyrosine kinase inhibitor tucatinib as a single agent or in combination with trastuzumab or docetaxel in solid tumor models
.
Mol Cancer Ther
2020
;
19
:
976
87
.
32.
Borges
VF
,
Ferrario
C
,
Aucoin
N
,
Falkson
C
,
Khan
Q
,
Krop
I
, et al
Tucatinib combined with ado-trastuzumab emtansine in advanced ERBB2/HER2-positive metastatic breast cancer: A Phase 1b Clinical Trial
.
JAMA Oncol
2018
;
4
:
1214
20
.
33.
Lin
NU
,
Borges
V
,
Anders
C
,
Murthy
RK
,
Paplomata
E
,
Hamilton
E
, et al
Intracranial efficacy and survival with tucatinib plus trastuzumab and capecitabine for previously treated HER2-positive breast cancer with brain metastases in the HER2CLIMB Trial
.
J Clin Oncol
2020
;
38
:
2610
9
.
34.
Murthy
RK
,
Loi
S
,
Okines
A
,
Paplomata
E
,
Hamilton
E
,
Hurvitz
SA
, et al
Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer
.
N Engl J Med
2020
;
382
:
586
.
35.
Wen
PY
,
Yung
WKA
,
Lamborn
KR
,
Dahia
PL
,
Wang
Y
,
Peng
B
, 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
907
.
36.
Batchelor
TT
,
Duda
DG
,
di Tomaso
E
,
Ancukiewicz
M
,
Plotkin
SR
,
Gerstner
E
, et al
Phase II study of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma
.
J Clin Oncol
2010
;
28
:
2817
23
.
37.
Iwamoto
FM
,
Lamborn
KR
,
Robins
HI
,
Mehta
MP
,
Chang
SM
,
Butowski
NA
, et al
Phase II trial of pazopanib (GW786034), an oral multi-targeted angiogenesis inhibitor, for adults with recurrent glioblastoma (North American Brain Tumor Consortium Study 06–02)
.
Neuro Oncol
2010
;
12
:
855
61
.
38.
Xiao
TM
,
Yang
L
,
Su
Y
,
Vemireddy
V
,
Guntipalli
P
,
Ramachandran
A
,
Chaudhary
P
, et al
Preclinical evaluation of CP868,596, a novel PDGFRα Inhibitor for treatment of glioblastoma [abstract]
.
In
:
Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research
; 
2011
Apr 2–6
;
Orlando, FL. Philadelphia (PA)
:
AACR
;
Cancer Res 2011
;
71
(
8 Suppl
):
Abstract nr 1111
.
39.
Cheng
F
,
Guo
D
. 
MET in glioma: signaling pathways and targeted therapies
.
J Exp Clin Cancer Res
2019
;
38
:
270
.
40.
Zhang
Y
,
Guessous
F
,
Kofman
A
,
Schiff
D
,
Abounader
R
. 
XL-184, a MET, VEGFR-2 and RET kinase inhibitor for the treatment of thyroid cancer, glioblastoma multiforme and NSCLC
.
IDrugs
2010
;
13
:
112
21
.
41.
Reardon
DA
,
Turner
S
,
Peters
KB
,
Desjardins
A
,
Gururangan
S
,
Sampson
JH
, et al
A review of VEGF/VEGFR-targeted therapeutics for recurrent glioblastoma
.
J Natl Compr Canc Netw
2011
;
9
:
414
27
.
42.
Wen
PY
,
Drappatz
J
,
de Groot
J
,
Prados
MD
,
Reardon
DA
,
Schiff
D
, et al
Phase II study of cabozantinib in patients with progressive glioblastoma: subset analysis of patients naive to antiangiogenic therapy
.
Neuro Oncol
2018
;
20
:
249
58
.
43.
Taal
W
,
Oosterkamp
HM
,
Walenkamp
AME
,
Dubbink
HJ
,
Beerepoot
LV
,
Hanse
MCJ
, et al
Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial
.
Lancet Oncol
2014
;
15
:
943
53
.
44.
Sandmann
T
,
Bourgon
R
,
Garcia
J
,
Li
C
,
Cloughesy
T
,
Chinot
OL
, et al
Patients with proneural glioblastoma may derive overall survival benefit from the addition of bevacizumab to first-line radiotherapy and temozolomide: retrospective analysis of the AVAglio Trial
.
J Clin Oncol
2015
;
33
:
2735
44
.
45.
Wen
PY
,
Cloughesy
TF
,
Olivero
AG
,
Morrissey
KM
,
Wilson
TR
,
Lu
X
, et al
First-in-human phase I study to evaluate the brain-penetrant PI3K/mTOR Inhibitor GDC-0084 in patients with progressive or recurrent high-grade glioma
.
Clin Cancer Res
2020
;
26
:
1820
8
.
46.
Wen
PY
,
Rodon
JA
,
Mason
W
,
Beck
JT
,
DeGroot
J
,
Donnet
V
, et al
Phase I, open-label, multicentre study of buparlisib in combination with temozolomide or with concomitant radiation therapy and temozolomide in patients with newly diagnosed glioblastoma
.
ESMO Open
2020
;
5
:
e000673
.
47.
Fonkem
E
,
Wong
ET
. 
NovoTTF-100A: a new treatment modality for recurrent glioblastoma
.
Expert Rev Neurother
2012
;
12
:
895
9
.
48.
Stupp
R
,
Wong
ET
,
Kanner
AA
,
Steinberg
D
,
Engelhard
H
,
Heidecke
V
, et al
NovoTTF-100A versus physician's choice chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment modality
.
Eur J Cancer
2012
;
48
:
2192
202
.
49.
Stupp
R
,
Taillibert
S
,
Kanner
A
,
Read
W
,
Steinberg
DM
,
Lhermitte
B
, et al
Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: a randomized clinical trial
.
JAMA
2017
;
318
:
2306
16
.
50.
Chen
L
,
Han
X
. 
Anti-PD-1/PD-L1 therapy of human cancer: past, present, and future
.
J Clin Invest
2015
;
125
:
3384
91
.
51.
Wang
X
,
Guo
G
,
Guan
H
,
Yu
Y
,
Lu
J
,
Yu
J
. 
Challenges and potential of PD-1/PD-L1 checkpoint blockade immunotherapy for glioblastoma
.
J Exp Clin Cancer Res
2019
;
38
:
87
.
52.
Garon
EB
,
Rizvi
NA
,
Hui
R
,
Leighl
N
,
Balmanoukian
AS
,
Eder
JP
, et al
Pembrolizumab for the treatment of non-small-cell lung cancer
.
N Engl J Med
2015
;
372
:
2018
28
.
53.
Robert
C
,
Schachter
J
,
Long
GV
,
Arance
A
,
Grob
JJ
,
Mortier
L
, et al
Pembrolizumab versus ipilimumab in advanced melanoma
.
N Engl J Med
2015
;
372
:
2521
32
.
54.
Marcus
L
,
Lemery
SJ
,
Keegan
P
,
Pazdur
R
. 
FDA Approval summary: Pembrolizumab for the treatment of microsatellite instability-high solid tumors
.
Clin Cancer Res
2019
;
25
:
3753
8
.
55.
Caccese
M
,
Indraccolo
S
,
Zagonel
V
,
Lombardi
G
. 
PD-1/PD-L1 immune-checkpoint inhibitors in glioblastoma: a concise review
.
Crit Rev Oncol Hematol
2019
;
135
:
128
34
.
56.
Reardon
DA
,
Brandes
AA
,
Omuro
A
,
Mulholland
P
,
Lim
M
,
Wick
A
, et al
Effect of nivolumab vs bevacizumab in patients with recurrent glioblastoma: the CheckMate 143 Phase 3 Randomized Clinical Trial
.
JAMA Oncol
2020
;
6
:
1003
10
.
57.
Migliorini
D
,
Dietrich
P-Y
,
Stupp
R
,
Linette
GP
,
Posey
AD
,
June
CH
. 
CAR T-cell therapies in glioblastoma: a first look
.
Clin Cancer Res
2018
;
24
:
535
40
.
58.
Uyttenhove
C
,
Pilotte
L
,
Théate
I
,
Stroobant
V
,
Colau
D
,
Parmentier
N
, et al
Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase
.
Nat Med
2003
;
9
:
1269
74
.
59.
Zhai
L
,
Ladomersky
E
,
Lauing
KL
,
Wu
M
,
Genet
M
,
Gritsina
G
, et al
Infiltrating T CELLS INCrease IDO1 expression in glioblastoma and contribute to decreased patient survival
.
Clin Cancer Res
2017
;
23
:
6650
60
.
60.
Naour
JL
,
Galluzzi
L
,
Zitvogel
L
,
Kroemer
G
,
Vacchelli
E
. 
Trial watch: IDO inhibitors in cancer therapy
.
Oncoimmunology
2020
;
9
:
1777625
.
61.
Ladomersky
E
,
Zhai
L
,
Lenzen
A
,
Lauing
KL
,
Qian
J
,
Scholtens
DM
, et al
IDO1 inhibition synergizes with radiation and PD-1 blockade to durably increase survival against advanced glioblastoma
.
Clin Cancer Res
2018
;
24
:
2559
73
.
62.
Alphandery
E
. 
Nano-therapies for glioblastoma treatment
.
Cancers (Basel)
2020
;
12
:
242
.
63.
Ciregia
F
,
Urbani
A
,
Palmisano
G
. 
Extracellular vesicles in brain tumors and neurodegenerative diseases
.
Front Mol Neurosci
2017
;
10
:
276
.
64.
Kooijmans
SAA
,
Aleza
CG
,
Roffler
SR
,
van Solinge
WW
,
Vader
P
,
Schiffelers
RM
. 
Display of GPI-anchored anti-EGFR nanobodies on extracellular vesicles promotes tumour cell targeting
.
J Extracell Vesicles
2016
;
5
:
31053
.
65.
Skog
J
,
Würdinger
T
,
van Rijn
S
,
Meijer
DH
,
Gainche
L
,
Curry
WT
, et al
Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers
.
Nat Cell Biol
2008
;
10
:
1470
6
.
66.
Harshyne
LA
,
Hooper
KM
,
Andrews
EG
,
Nasca
BJ
,
Kenyon
LC
,
Andrews
DW
, et al
Glioblastoma exosomes and IGF-1R/AS-ODN are immunogenic stimuli in a translational research immunotherapy paradigm
.
Cancer Immunol Immunother
2015
;
64
:
299
309
.
67.
Akers
JC
,
Ramakrishnan
V
,
Kim
R
,
Skog
J
,
Nakano
I
,
Pingle
S
, et al
MiR-21 in the extracellular vesicles (EVs) of cerebrospinal fluid (CSF): a platform for glioblastoma biomarker development
.
PLoS One
2013
;
8
:
e78115
.
68.
Akers
JC
,
Ramakrishnan
V
,
Kim
R
,
Phillips
S
,
Kaimal
V
,
Mao
Y
, et al
miRNA contents of cerebrospinal fluid extracellular vesicles in glioblastoma patients
.
J Neurooncol
2015
;
123
:
205
16
.
69.
Zeng
A
,
Wei
Z
,
Yan
W
,
Yin
J
,
Huang
X
,
Zhou
X
, et al
Exosomal transfer of miR-151a enhances chemosensitivity to temozolomide in drug-resistant glioblastoma
.
Cancer Lett
2018
;
436
:
10
21
.
70.
Zhang
Q
,
Liu
F
. 
Advances and potential pitfalls of oncolytic viruses expressing immunomodulatory transgene therapy for malignant gliomas
.
Cell Death Dis
2020
;
11
:
485
.
71.
Patel
DM
,
Foreman
PM
,
Nabors
LB
,
Riley
KO
,
Gillespie
GY
,
Markert
JM
. 
Design of a Phase I clinical trial to evaluate M032, a genetically engineered HSV-1 Expressing IL-12, in patients with recurrent/progressive glioblastoma multiforme, anaplastic astrocytoma, or gliosarcoma
.
Hum Gene Ther Clin Dev
2016
;
27
:
69
78
.
72.
Wohlfahrt
ME
,
Beard
BC
,
Lieber
A
,
Kiem
HP
. 
A capsid-modified, conditionally replicating oncolytic adenovirus vector expressing TRAIL leads to enhanced cancer cell killing in human glioblastoma models
.
Cancer Res
2007
;
67
:
8783
90
.
73.
Li
X
,
Mao
Q
,
Wang
D
,
Zhang
W
,
Xia
H
. 
A fiber chimeric CRAd vector Ad5/11-D24 double-armed with TRAIL and arresten for enhanced glioblastoma therapy
.
Hum Gene Ther
2012
;
23
:
589
96
.
74.
Yacoub
A
, et al
Melanoma differentiation-associated 7 (interleukin 24) inhibits growth and enhances radiosensitivity of glioma cells in vitro and in vivo
.
Clin Cancer Res
2003
;
9
:
3272
81
.
75.
Kim
JH
,
Oh
JY
,
Park
BH
,
Lee
DE
,
Kim
JS
,
Park
HE
, et al
Systemic armed oncolytic and immunologic therapy for cancer with JX-594, a targeted poxvirus expressing GM-CSF
.
Mol Ther
2006
;
14
:
361
70
.
76.
Passaro
C
,
Alayo
Q
,
DeLaura
I
,
McNulty
J
,
Grauwet
K
,
Ito
H
, et al
Arming an oncolytic herpes simplex virus type 1 with a single-chain fragment variable antibody against pd-1 for experimental glioblastoma therapy
.
Clin Cancer Res
2019
;
25
:
290
9
.
77.
Sonabend
AM
,
Ulasov
IV
,
Tyler
MA
,
Rivera
AA
,
Mathis
JM
,
Lesniak
MS
. 
Mesenchymal stem cells effectively deliver an oncolytic adenovirus to intracranial glioma
.
Stem Cells
2008
;
26
:
831
41
.
78.
Tyler
MA
,
Ulasov
IV
,
Sonabend
AM
,
Nandi
S
,
Han
Y
,
Marler
S
, et al
Neural stem cells target intracranial glioma to deliver an oncolytic adenovirus in vivo
.
Gene Ther
2009
;
16
:
262
78
.
79.
Frederick
NDT
,
Lang
F
,
Vinay
K
,
Puduvalli
JB
,
Elder
KL
,
Fink
CA
, et al
Phase 1b open-label randomized study of the oncolytic adenovirus DNX-2401 administered with or without interferon gamma for recurrent glioblastoma
.
J Clin Oncol
35
:
15s
, 
2017
(
suupl. abstr. 2002
).
80.
Sasmita
AO
,
Wong
YP
,
Ling
APK
. 
Biomarkers and therapeutic advances in glioblastoma multiforme
.
Asia Pac J Clin Oncol
2018
;
14
:
40
51
.
81.
Greig
SL
. 
Osimertinib: First global approval
.
Drugs
2016
;
76
:
263
73
.
82.
Jardim
DL
,
Schwaederle
M
,
Hong
DS
,
Kurzrock
R
. 
An appraisal of drug development timelines in the Era of precision oncology
.
Oncotarget
2016
;
7
:
53037
46
.
83.
Jun
HJ
,
Acquaviva
J
,
Chi
D
,
Lessard
J
,
Zhu
H
,
Woolfenden
S
, et al
Acquired MET expression confers resistance to EGFR inhibition in a mouse model of glioblastoma multiforme
.
Oncogene
2012
;
31
:
3039
50
.
84.
Engelman
JA
,
Zejnullahu
K
,
Mitsudomi
T
,
Song
Y
,
Hyland
C
,
Park
JO
, et al
MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling
.
Science
2007
;
316
:
1039
43
.
85.
Narayan
RS
,
Molenaar
P
,
Teng
J
,
Cornelissen
FMG
,
Roelofs
I
,
Menezes
R
, et al
A cancer drug atlas enables synergistic targeting of independent drug vulnerabilities
.
Nat Commun
2020
;
11
:
2935
.
86.
Malyutina
A
,
Majumder
MM
,
Wang
W
,
Pessia
A
,
Heckman
CA
,
Tang
J
. 
Drug combination sensitivity scoring facilitates the discovery of synergistic and efficacious drug combinations in cancer
.
PLoS Comput Biol
2019
;
15
:
e1006752
.
87.
Sidorov
P
,
Naulaerts
S
,
Ariey-Bonnet
J
,
Pasquier
E
,
Ballester
PJ
. 
Predicting synergism of cancer drug combinations using NCI-ALMANAC data
.
Front Chem
2019
;
7
:
509
.